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Meiosis: cell-cycle controls shuffle and deal
Author: A. L. Marston
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"� 2004 Nature Publishing Group Meiosis is a specialized type of cell division that gener- ates gametes with a haploid set of chromosomes. By contrast, mitosis produces daughter cells with a chro- mosome complement that is identical to that of the progenitor cell. The generation of haploid gametes requires both general cell-cycle regulators and meiosis- specific proteins. In this review, we will discuss how the mitotic cell-cycle machinery is modulated to bring about the meiotic programme, with particular empha- sis on the modifications that result in the specialized meiotic chromosome-segregation programme (FIG. 1). Although the meiotic programme is not, strictly speak- ing, a cell cycle, in this review we will refer to the events from the decision to enter the meiotic programme up until the generation of gametes as the meiotic cell cycle, because many of the key regulators of the mitotic cell cycle control this process. First, we will discuss the controls that regulate the decision to embark on either the meiotic or the mitotic cell cycle and how these regulatory pathways control the G1?S-phase transition. We will then compare and contrast the pre-meiotic and pre-mitotic S phases. Next, we will summarize the aspects of meiotic G2 that are relevant to cell-cycle control, followed by a detailed discussion of the controls that bring about the unique pattern of chromosome segregation during meiosis I and leave in place the tools to segregate chro- mosomes during meiosis II. We will end with an overview of the regulatory circuits that control the specialized meiosis-I?meiosis-II transition and meio- sis-II chromosome segregation. For some other aspects of the meiotic cell cycle, such as the pairing of HOMOLOGUES,meiotic recombination and developmen- tal signals that control progression through meiosis, the reader will be referred to recent reviews. Our dis- cussion focuses primarily on studies that have been conducted in the fission yeast (Schizosaccharomyces pombe) and the budding yeast (Saccharomyces cere- visiae), and for this reason, yeast nomenclature is used, but for the corresponding gene and protein names in other organisms, please see TABLES 1,2. Regulation of the meiotic G1?S-phase transition The decision to enter the meiotic cell cycle occurs in response to cues that vary greatly among different organisms. In multicellular organisms, extrinsic cues from surrounding cells control the differentiation of germline stem cells that will enter the meiotic cell cycle. The molecular mechanisms that regulate this differentiation process are largely unknown 1?3 .In bud- ding and fission yeast, poor nutrient conditions are the cue to embark on the meiotic cell cycle, which culmi- nates in the production of spores 4,5 .The decision to enter the meiotic cell cycle is made in G1 phase and this affects the way in which the G1?S transition is controlled. In budding yeast, nutrient limitation culminates in the expression of two principal regulators of meiotic initiation, inducer of meiosis (IME)1 and IME2,which promote entry into pre-meiotic S phase. These meiotic regulators substitute for the CYCLIN-DEPENDENT KINASE (CDK) Cdc28,which, when in complex with G1 cyclins (Clns), promotes entry into the mitotic cell cycle (FIG. 2).Ime1 is a transcription factor that initiates a MEIOSIS: CELL-CYCLE CONTROLS SHUFFLE AND DEAL Ad�le L. Marston and Angelika Amon Abstract | Meiosis is the type of cell division that gives rise to eggs and sperm. Errors in the execution of this process can result in the generation of aneuploid gametes, which are associated with birth defects and infertility in humans. Here, we review recent findings on how cell-cycle controls ensure the coordination of meiotic events, with a particular focus on the segregation of chromosomes. NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | DECEMBER 2004 | 983 Center for Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, E17-233, 40 Ames Street, Cambridge, Massachusetts 02139, USA. Correspondence to A.A. e-mail: angelika@mit.edu doi:10.1038/nrm1526 HOMOLOGUE One member of a chromosome pair (where each member of the pair is derived from one parent) in diploid organisms. CYCLIN-DEPENDENT KINASE (CDK). A protein kinase that requires an associated cyclin protein for activity. Various CDK?cyclin complexes regulate different stages of the cell cycle. REVIEWS � 2004 Nature Publishing Group APC/C (Anaphase-promoting complex/cyclosome). A ubiquitin ligase which, together with a ubiquitin-conjugating enzyme, attaches ubiquitin peptides to a substrate protein. Ubiquitylated proteins are recognized by the 26S proteasome and are subsequently degraded. SYNAPTONEMAL COMPLEX (SC). A proteinaceous structure that forms between two homologues during meiotic G2, which is defined by a state of low CDK activity (when chromosomes are condensed ? cytologically speaking, this is prophase). COHESIN A protein complex that tethers sister chromatids together. SISTER CHROMATIDS Chromosomes that have been duplicated during S phase. MITOTIC/MEIOTIC SPINDLE A bipolar array of microtubules that forms during mitosis and meiosis to which chromosomes attach and by which chromosomes are segregated to daughter cells. 984 | DECEMBER 2004 | VOLUME 5 www.nature.com/reviews/molcellbio REVIEWS Sphase in many respects. The same origins and replica- tive machinery are used and replication forks progress at similar rates 17?20 , at least in budding yeast. However, despite the usage of the same replicative machinery and regulators that control its activity during pre-mitotic and pre-meiotic DNA replication, there are likely to be differences between pre-mitotic and pre-meiotic DNA replication. In all organisms analysed so far, pre-meiotic S phase is substantially longer than pre-mitotic S phase 21 , and factors such as the budding yeast gene MUM2 have been found to be essential for pre-meiotic DNA replica- tion, but not for pre-mitotic replication 22 . Lengthening of S phase and the use of additional fac- tors during pre-meiotic S phase ? in comparison with pre-mitotic S phase ? might be necessary because interactions between homologue pairs, which are neces- sary for their faithful segregation during meiosis I, are initiated during pre-meiotic S phase. Several studies in yeast have established a require- ment for passage through S phase to establish inter- homologue interactions such as meiotic recombina- tion 23,24 , pairing of homologues 24 and the formation of the SYNAPTONEMAL COMPLEX (SC) 24 .Meiotic recombination begins with the deliberate introduction of DNA double- strand breaks (DSBs) by the transesterase sporulation protein (Spo)11 (REFS 25,26).This event requires DNA replication and occurs after bulk DNA synthesis 23,27 . Budding yeast clb5 clb6 mutants that fail to undergo bulk pre-meiotic DNA synthesis 15 generate DSBs and SCs at levels that are proportional to the amount of DNA synthesis in these mutants 24 .Furthermore, when all origins of replication are deleted on the left arm of chromosome III, this chromosome arm replicates late during S phase and DSB formation is delayed to a simi- lar degree 23 .In fission yeast, however, mutants that fail to complete DNA synthesis were found to form DSBs at appreciable levels 28 .This could be because DSB forma- tion is controlled differently in the two yeasts or, alterna- tively, it is possible that the observed DSBs correspond to the replicated part of the genome. The requirement for passage through S phase for recombination and homologue pairing is explained by the fact that COHESIN, the protein complex that holds duplicated chromosomes (SISTER CHROMATIDS) together, has an essential role in these processes 29,30 .At least in fission yeast, cohesin must be laid down during S phase to sup- port inter-homologue interactions 31 .Although it has not been shown directly, there is likely to be a similar situation in budding yeast. Passage through pre-mitotic Sphase has been shown to be essential for cohesin to be functional 32 . Meiotic G2 Meiotic G2 is defined by a state of low meiotic CDK activity. During this cell-cycle stage, linkages between homologue pairs are generated to ensure their co-align- ment on the meiosis-I SPINDLE in preparation for segre- gation during meiosis I. For chromosomes of most, although not all, organisms, this linkage is brought about by at least one CHIASMA,which is generated as a result of meiotic recombination between the homologous transcriptional programme that allows meiotic regula- tors to be generated in a temporally defined manner 6,7 . A key target of Ime1 is the IME2 gene, which encodes a meiosis-specific kinase with homology to CDKs. Ime2 promotes entry into pre-meiotic S phase by carrying out some of the functions of Cln?CDKs (FIG. 2). Degradation of the S-phase CDK inhibitor, subunit inhibitor of CDK (Sic)1, is dependent on IME2 (REF. 8). Ime2 also inhibits the ubiquitin-dependent proteolysis machinery that is defined by its ubiquitin ligase ? the anaphase-promoting complex/cyclosome (APC/C) ? thereby allowing the stabilization of cyclin B (Clb) cyclins, which promote S phase and chromosome segre- gation 9 (FIG. 2). In fission yeast, entry into the meiotic cell cycle is prevented by the protein kinase Pat1.Pat1 blocks meio- sis by phosphorylating the RNA-binding protein Mei2, the activation of which is, in itself, sufficient to initiate the meiotic programme 10,11 .In response to meiosis-induc- ing conditions, a specific Pat1 inhibitor, Mei3,is expressed ? this releases the repression of Mei2 by Pat1 and initiates meiotic progression 12,13 .Mei2 cooperates with a specific small RNA, meiRNA 14 ;however, the precise molecular function of Mei2 is unknown. Pre-meiotic S phase After cells have committed to the meiotic cell cycle, they undergo pre-meiotic S phase. In budding yeast, pre- mitotic as well as pre-meiotic DNA replication is trig- gered by S-phase CDKs, which are composed of the two B-type cyclins Clb5 and Clb6, and Cdc28 (REFS 8,15,16). Pre-meiotic DNA replication resembles pre-mitotic Figure 1 | The mitotic and meiotic cell cycles. a | In mitosis, diploid cells replicate chromosomes during S phase and segregate sister chromatids during M phase, so that diploid daughter cells are produced. b | In meiosis, two chromosome-segregation phases, meiosis I and meiosis II, follow a single round of DNA replication during pre-meiotic S phase. During meiosis I, homologous chromosomes (shown in red and blue) are segregated to opposite poles. Sister chromatids segregate to opposite poles during meiosis II, which results in the formation of non-identical haploid gametes. Please note that the lengths of the cell-cycle stages are not drawn to scale. G1 S MG2 G1 Diploid Diploid Homologues Sister chromatids G1 S Meiosis I G2 Meiosis II Diploid Haploid Homologues segregate Sister chromatids segregate Chiasma a b Homologues Sister chromatids � 2004 Nature Publishing Group NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | DECEMBER 2004 | 985 REVIEWS activation and the continuation of the developmental programme of meiosis (spore formation) by down- regulating meiotic gene expression. CDKs are inhibited by the recombination checkpoint through activation of Saccharomyces Wee1 (Swe1), which phosphorylates Cdc28 on Tyr19, thereby inhibiting its activity 44 .Furthermore, transcription of the meiotic cyclins CLB1, CLB3 and CLB4 is prevented because the transcription factor Ndt80,which transcribes a large set of meiotic genes during G2, is inhibited, and the repressor of these genes, suppressor of Mar1 (Sum)1, is active 45?47 .The downregulation of Ndt80- dependent transcription also ensures that the devel- opmental programme does not proceed, thereby establishing a complete G2 arrest until all DNA dam- age has been repaired. The recombination checkpoint is not the only signal that halts meiotic cell-cycle progression in G2. In the female germline of most metazoans, developmental signals induce a G2 arrest. Oocytes arrest in G2 (diplotene) until their maturation is triggered during ovulation later in the life of the organism. The molecu- lar mechanisms that control this cell-cycle arrest and the resumption of meiosis are complex and, in part, controversial, so we direct readers to reviews by experts in this field 48,49 . Meiosis I: a unique segregation event Once recombination has been completed, cells enter the meiotic divisions. Meiosis I is a unique type of chromo- some-segregation event because it is the homologue pairs that segregate from each other, rather than the sister chromatids, as occurs in mitosis and meiosis II (BOX 1; FIG. 1).For this specialized segregation to occur and leave in place the tools to segregate sister chromatids during meiosis II, the mitotic chromosome-segregation machinery (summarized in BOX 1) must be modified in three ways (FIG. 4). First, homologue pairs must be linked, chromosomes. We will only discuss the relevance of recombination to chromosome segregation and cell- cycle progression (see REFS 33?35 for recent reviews on the mechanistic details of meiotic recombination). Meiotic recombination is initiated upon the intro- duction of DSBs by Spo11 (REFS 25,26).These DSBs can be processed to generate two types of recombination product ? either a crossover (CO), in which recipro- cal exchange between homologue pairs has occurred, or a non-crossover (NCO), in which reciprocal exchange has not occurred. Recent studies in budding yeast have shown the existence of two different recom- bination pathways for the processing of DSBs. One pathway generates only COs and an alternative path- way, predominantly generates NCOs 36,37 (FIG. 3).The decision to generate a CO or an NCO is made soon after DSB formation 35,37?39 .Importantly, only COs result in the linking of homologue pairs. As these linkages are essential for the proper segregation of homologue pairs during meiosis I, elucidating the mechanisms that ensure the presence of at least one CO per pair of homologues will be crucial to under- stand how homologue segregation is regulated. Recombination causes severe DNA damage. It is therefore essential that meiosis-I chromosome segre- gation does not proceed until all damage has been repaired. One or more surveillance mechanisms ensure that this is the case 40 .The recombination, or pachytene, checkpoint is one such surveillance mech- anism. It is activated concomitant with, or shortly after, DSB formation and delays entry into meiosis I until all DSBs have been repaired. The checkpoint is most well-characterized in budding yeast 40,41 but is likely to exist in other organisms, as mouse spermato- cytes and oocytes that are deficient for the recombina- tion factor Dmc1, and therefore fail to repair DSBs, arrest in G2 42,43 .The recombination checkpoint pre- vents entry into meiosis I by preventing meiotic CDK CHIASMA (plural: chiasmata). Cytological manifestation of the point of exchange or crossing over between two homologues due to meiotic recombination. Table 1 | Conservation of the cohesin complex across species in mitosis and meiosis* Developmental Sc Sp At Ce Dm Xl Mammals References cycle Mitosis Scc1(Mcd1) Rad21 - SCC-1/COH-2 DRAD21 XRAD21 RAD21/HR21sp/PW29 129?132,134, 166?171 Scc3/Irr1 Psc3 - SCC-3 DSA XSA1, SA1/STAG1, 59,132,134,139,166, XSA2 SA2/STAG2 167,169,170,178 Smc1 Psm1 - HIM-1/SMC-1 DSMC1 XSMC1 SMC1?/mSMCB 130?132,134,166,167, 169?172 Smc3 Psm3 - SMC-3 DSMC3 XSMC3 SMC3/mSMCD 130?132,134,166,167, 169?172 Meiosis Rec8 ? Rec8 ? SYN1?DIF1 ? REC-8 ? -- REC8 ? , 30,56?58,173?177,180 RAD21/SCC1 Scc3 Psc3 � ,- SCC-3 - - SA2/STAG2 59,139,174,178?180 Rec11 ?|| SA3/STAG3 ?|| Smc1 Psm1 - SMC-1 - - SMC1? ? 57,58,180,181 Smc3 Psm3 - SMC-3 - - SMC3 30,57,58,130,180 *Potential cohesin complexes in mitosis and meiosis are shown based on the available functional or cytological data. ? Meiosis-specific proteins. � Proteins found to localize only to centromeric regions. || Proteins found to localize only to chromosome arms. At, Arabidopsis thaliana, Ce, Caenorhabditis elegans; COH-2, cohesin-2; Dm, Drosophila melanogaster; HR21sp, Homo sapiens Rad21; PW29, Pokeweed agglutinin-binding protein-29; Rec, recombination protein; Sc, Saccharomyces cerevisiae; Sp, Schizosaccharomyces pombe; SA/STAG, stromalin antigen; Scc, subunit of the cohesin complex; Smc, structural maintenance of chromosomes; Xl, Xenopus laevis. � 2004 Nature Publishing Group 986 | DECEMBER 2004 | VOLUME 5 www.nature.com/reviews/molcellbio REVIEWS Meiosis I: loss of arm cohesion As mentioned above, sister chromatids, which are gener- ated during S phase, are held together by a protein com- plex that is known as cohesin, which is thought to form a ring around the duplicated DNA 54 .During the mitotic as well as the meiotic cell cycle, cohesins must be assembled onto the DNA during DNA replication for them to func- tion as cohesion factors 31,32 (BOX 1).During mitosis, cleav- age of one of the cohesin subunits, Scc1(Mcd1)/Rad21 (the budding yeast protein subunit of the cohesin com- plex (Scc)1 is encoded by the MCD1 gene; Rad21 is the Scc1 homologue in fission yeast), by a protease that is known as SEPARASE initiates mitotic chromosome segre- gation (BOX 1). During meiosis, the existence of two consecutive rounds of chromosome segregation requires that cohe- sion between sister chromatids is lost in a stepwise man- ner. Loss of cohesion on chromosome arms in meiosis I abolishes the linkage between homologue pairs and allows them to separate to opposite poles of the meiosis-I spindle. Cohesion between sister chromatids is, how- ever, maintained around the centromeric regions to ensure that they do not drift apart before anaphase II and to promote the proper attachment of sister chro- matids to the meiosis-II spindle. This stepwise loss of cohesion requires some changes to the cohesin complex itself and the way it is regulated. A conserved modification of the meiotic cohesin complex is the substitution of the Scc1(Mcd1)/Rad21 usually by chiasmata, to ensure their alignment on the meiosis-I spindle. Second, some linkage (COHESION) between sister chromatids must be maintained beyond meiosis I to prevent their premature dissociation and ensure their proper attachment to the meiosis-II spindle. Third, sister chromatids have to attach to microtubules that emanate from the same SPINDLE POLE in meiosis I, but from opposite poles in meiosis II. Chiasmata hold homologues together. Chiasmata are gen- erated as a result of reciprocal recombination between homologue pairs, and they hold the pairs together. This allows the BIVALENT (a pair of recombined homologues) to align correctly on the meiosis-I spindle (FIG. 4).The importance of chiasmata for accurate meiosis-I chromo- some segregation has been shown by the observation that budding yeast and nematode worm (Caenorhabditis elegans) mutants that lack SPO11 ? and therefore do not initiate meiotic recombination ? randomly segregate their homologues at meiosis I 26,30,50 .In fission yeast, the inactivation of the Spo11 homologue, Rec12,results in near-random segregation at meiosis I (REF. 51), and Spo11 is also essential to generate functional gametes in the mouse 52,53 .Sister-chromatid cohesion on chromosome arms, distal to chiasmata, stabilizes the homologue inter- actions that are mediated by chiasmata. As described below, the loss of chromosome-arm cohesion is the single event that is required to allow homologues to segregate from each other during meiosis I. COHESION The sticking together of two sister chromatids. SPINDLE POLE The yeast equivalent of the centrosome that nucleates microtubules, including those that will form the spindle. BIVALENT A pair of homologues that are linked together following meiotic G2, which is defined by a state of low CDK activity (when chromosomes are condensed ? cytologically speaking, this is prophase). SEPARASE An enzyme that cleaves the cohesin subunit Scc1 or Rec8 during mitosis and meiosis. Table 2 | Gene names of key cell-cycle regulators Generic name Sc Sp Ce Xl Dm Mammalian G1 cyclin-dependent- CDC28?CLN1, cdc2?cig1, cdc2?puc1 -- - Cdk4?cyclin-D, kinase complex CDC28?CLN2, Cdk6?cyclin-D, CDC28?CLN3 Cdk2?cyclin-E S-phase cyclin- CDC28?CLB5, cdc2?cig2 -- - Cdk2?cyclin-A, dependent-kinase CDC28?CLB6 Cdk2?cyclin-E complex M-phase cyclin- CDC28?CLB1, cdc2?cdc13 -- - Cdk1?cyclin-B, dependent-kinase CDC28?CLB2, Cdk1?cyclin-A complex CDC28?CLB3, CDC28?CLB4 - MIH1 cdc25 CDC-25 CDC25 String CDC25A,CDC25B, CDC25C - SWE1 wee1 WEE-1 WEE1 WEE WEE1 Separase ESP1 cut1 SEP-1 - Three Rows (THR), ESPL1 Separase (SSE) Securin PDS1 cut2 IFY-1 PTTG Pimples (PIM) PTTG1 - SPO11 rec12 SPO-11 - MEI-W68 SPO11 Shugoshin SGO1 sgo1 - - MEI-S332 - Polo kinase CDC5 plo1 PLK-2 PLX1 POLO PLK1 Aurora kinase - - AIR-1 Aurora-A (Eg2) Aurora-A Aurora-A IPL1 ark1 AIR-2 Aurora-B Aurora-B Aurora-B -- --- Aurora-C - CDC14 clp1 CDC-14 -- CDC14A, CDC14B - MAD2 mad2 MDF-2 MAD2 MAD2 MAD2L1, MAD2L2 AIR, Aurora/Ipl1-related kinase; ark1, aurora kinase-1; Cdk, cyclin-dependent kinase; Ce, Caenorhabditis elegans; CLB, cyclin B; CLN, cyclin; clp1, Cdc14-related protein phosphatase-1; Dm, Drosophila melanogaster; ESP1, extra spindle poles-1; ESPL1, extra spindle poles-like-1; IFY-1, interactor of FZY-1; MAD2, mitotic arrest-deficient-2; MDF-2, yeast mitosis-arrest-deficient related-2; MIH1, mitotic inducer homologue-1; PDS1, prevents the dissociation of sisters-1; PLK/plo/PLX/POLO, polo kinase; PTTG, pituitary tumor-transforming protein; Rec, recombination protein; Sc, Saccharomyces cerevisiae; SEP-1, separase-1; Sp, Schizosaccharomyces pombe; SGO1; shugoshin-1; SPO, sporulation protein; Swe1, Saccharomyces Wee1; Xl, Xenopus laevis. � 2004 Nature Publishing Group NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | DECEMBER 2004 | 987 REVIEWS subunit is found in cohesin complexes around cen- tromeres but is replaced on chromosome arms with a meiosis-specific variant, Rec11 (REF. 59) (TABLE 1).This specialization of arm cohesin could contribute to the differential timing with which arm and centromeric cohesins are lost in meiosis. Furthermore, Rec11, like Rec8, has a role in meiotic recombination that cannot be fulfilled by its mitotic counterpart 30,60,61 .Perhaps these cohesin-subunit variants promote inter-homo- logue invasion during recombination rather than inva- sion into the sister chromatid (which is the way DSBs are repaired during the mitotic cell cycle). They might thereby facilitate the generation of chiasmata, which is essential for meiosis-I chromosome segregation. Meiosis I: regulators of cohesin loss The role of separase. One possible mechanism to allow for the differential loss of arm and centromeric cohesin would be to restrict separase activity to meiosis II and remove cohesins from chromosome arms in a separase- independent manner during meiosis I, which is akin to the non-proteolytic way in which cohesins are removed from chromosome arms during prophase in mammalian cells 62,63 (BOX 1).However, elegant experiments in budding and fission yeast showed that separase-dependent cleav- age of Rec8 triggers the loss of cohesins, and therefore chromosome segregation during meiosis I and meiosis II (REFS 64,65).Whether the loss of cohesin by separase cleav- age mediates the loss of arm cohesion in meiosis I and II in other eukaryotes is not known. However, a function for separase and its regulator, the ubiquitin ligase APC/C, in the segregation of homologues during meiosis I has also been shown in nematode worm 66,67 and mouse oocytes 68,69 ,which indicates that separase-dependent cleavage of Rec8 on chromosome arms is conserved. Curiously, however, destruction of the separase inhibitor SECURIN by the APC/C does not seem to be required for meiosis-I chromosome segregation in frog (Xenopus laevis) oocytes 70,71 ,which suggests that different controls may remove cohesins from chromosome arms in this organism. A role for Rec8. The fact that separase controls the loss of cohesion during both meiosis I and meiosis II, at least in budding and fission yeast, predicts that cohesin complexes around centromeres must be resistant to cleavage by separase during meiosis I. Factors that ?pro- tect? centromeric Rec8 from cleavage have to be present during meiosis I but removed before, or at, the onset of anaphase II. One important factor in the protection of centromeric cohesins is Rec8 itself. The replacement of Rec8 with Scc1(Mcd1)/Rad21 leads to the loss of cohesins along the entire length of chromosomes at the onset of anaphase I in budding and fission yeast 72,73 . This indicates that a property of Rec8 that is not shared with Scc1(Mcd1)/Rad21 is important for its protection at centromeres. One difference between Scc1(Mcd1) and Rec8 in budding yeast is their relative dependence on the Polo-like kinase Cdc5 for cleavage by separase. Phosphorylation of Scc1(Mcd1) by Cdc5 facilitates Scc1(Mcd1) cleavage, but is not essential 74 .By contrast, subunit with a meiosis-specific variant, Rec8 (TABLE 1). Rec8 is essential for sister-chromatid cohesion during meiosis in budding yeast, fission yeast and nematode worms 30,31,55 .Immunolocalization experiments showed that Rec8 is lost from chromosome arms during meiosis I, but retained around CENTROMERES until meiosis II in yeast 30,56 ,mice 57 and rats 58 .In nematode worms, in which the chromosomes are HOLOCENTRIC during mitosis, but become functionally MONOCENTRIC during meiosis, an equivalent, stepwise loss of cohesin occurs. In this organism, Rec8 is partially lost during meiosis I, but retained between the facultative centromere and the nearest crossover until meiosis II (REF. 55). In some organisms, there are several different cohesin complexes, of which some are specific to meiosis (TABLE 1).In fission yeast meiosis, the mitotic Psc3 CENTROMERE The region of the DNA on which the kinetochore assembles. HOLOCENTRIC CHROMOSOME A chromosome that has centromeres distributed along its length, which are known as diffuse centromeres. MONOCENTRIC CHROMOSOME A chromosome with a single centromere. SECURIN An inhibitor of separase that keeps the protease inactive until the onset of anaphase, at which point securin is destroyed, thereby liberating separase. Figure 2 | Cyclin-dependent-kinase activity in meiosis and mitosis. a | During G1, G1 cyclin-dependent kinase (CDK) activity (red) rises and induces the destruction of Sic1 and the inactivation of the anaphase-promoting complex/cyclosome (APC/C), thereby allowing entry into the cell cycle and the accumulation of S-phase CDK activity (green). S-phase CDKs initiate DNA replication 163,164 . Mitotic CDKs (blue) promote entry into mitosis. At the end of mitosis, mitotic CDKs are inactivated, which allows for the disassembly of the mitotic spindle and entry into G1. Inactivation of mitotic CDKs occurs through B-type-cyclin destruction 165 . b | During the meiotic cell cycle, a G1-like CDK (red; Ime2 in budding yeast) controls entry into the cell cycle and promotes the activation of S-phase CDKs (green; Cdc28?cyclin-B-5/6 (Clb5/6) in budding yeast) by inducing Sic1 destruction and inactivation of the APC/C. Ime2 has a second peak in kinase activity during the meiotic divisions and is required for the execution of the meiotic divisions 16 . It is not known if S-phase CDK activity declines after entry into meiosis I (dotted green line) 77 . Meiotic CDKs (blue; Cdc28?Clb1/3/4 in budding yeast) direct chromosome segregation during meiosis I. In the frog (Xenopus laevis), meiotic CDKs are partially inactivated between meiosis I and meiosis II, which prevents further DNA replication and chromosome segregation 113 . Meiotic CDK activity rises again to allow entry into meiosis II. Complete inactivation of meiotic CDKs triggers exit from meiosis II. Please note that the lengths of the cell-cycle stages are not drawn to scale. a b CDK activity CDK activity G1 G1 CDKs G1 CDKsS-phase CDKs Mitotic CDKs SMetaphase AnaphaseG2 G1 APC/C Sic1 APC/C G1-like CDKs S-phase CDKs Meiotic CDKs APC/C G1 S Meiosis I Meiosis IIG2 APC/C? ? ? Sic1 APC/C � 2004 Nature Publishing Group 988 | DECEMBER 2004 | VOLUME 5 www.nature.com/reviews/molcellbio REVIEWS impaired, although not completely deficient, in their ability to retain Rec8 at centromeres during meiosis I (REF. 30) and, when overproduced, Spo13 can prevent cleavage of Rec8 or Scc1(Mcd1), despite the fact that separase is active in these cells 78,79 .These results imply that Spo13 prevents the loss of centromeric cohesion; however, the question still remains how the region around the centromere is singled out for protection in meiosis I. The fruitfly (Drosophila melanogaster) protein MEI- S332 is ideally situated to function as a protein that pre- vents cohesin removal around centromeres during meiosis I. MEI-S332 localizes around centromeres but dissociates from these chromosomal regions at anaphase II, which corresponds to the time at which centromeric cohesion is lost in meiosis II (REF. 80,81). More importantly, in mei-S332 mutants, sister-chro- matid cohesion is lost prematurely 82 .Recently, three different genetic screens 83?85 identified a coiled-coil pro- tein, shugoshin (also known as Sgo1), that is distantly related to MEI-S332. Subsequently, Sgo1 homologues have been identified in almost all eukaryotes 84,86 . Like MEI-S332, budding yeast Sgo1 associates with KINETO- CHORES from G2 until metaphase II (REFS 83,85).In fission yeast, however, most Sgo1 dissociates from centromeric regions during anaphase I (REFS 84,86).The reason for this difference in behaviour is, at present, unclear. In sgo1? mutants of both yeasts, however, Rec8 is not retained at centromeric regions during meiosis I, and chromosomes segregate randomly at meiosis II (REFS 83?85).A key ques- tion is whether Sgo1 is required for the ability of the cohesin complex to establish cohesion at the cen- tromere, or whether Sgo1 functions as a ?protector? of cohesin, which ensures that cohesion is not lost until meiosis II. At least in fission yeast, Rec8 must be cleav- able by separase to allow sister chromatids to separate at meiosis II in an sgo1? mutant 86 .This finding sug- gests that cohesion is established at the centromere in the absence of SGO1, and that SGO1 regulates cohe- sion by preventing premature separase-dependent cleavage of Rec8 around centromeres. Elucidating the mechanism by which Sgo1 does this remains an impor- tant challenge for the future. Sgo1 could prevent access of separase to substrates or could prevent phosphoryla- tion of Rec8 by Cdc5, which would make Rec8 resistant to cleavage. Interestingly, MEI-S332 proteins also seem to function during mitosis. MEI-S332 is present during mitosis and might contribute to sister-chromatid cohesion in mitosis 87 . Fission yeast Sgo1 does not function in mitosis, but a second Sgo protein, which is known as Sgo2, is required for accurate chromo- some segregation in mitosis and, curiously, meiosis I but not meiosis II (REFS 84,86).In budding yeast, Sgo1 is also present at kinetochores during mitosis until the onset of anaphase and has an undefined role in chromosome segregation 83?85 .Although it is present during mitosis, Sgo1 does not prevent cohesin removal from centromeric regions during anaphase. This is probably due to the dissociation of Sgo1 from kinetochores at the onset of anaphase 83?85 .Therefore, Rec8 is absolutely dependent on Cdc5 for cleavage 75,76 , although it is not known whether Cdc5-dependent phosphorylation of Rec8 is important for cleavage. One attractive hypothesis is that Cdc5 is inhibited from phosphorylating cohesins around the centromere, which leaves Rec8 refractory to cleavage by separase in this region. Substituted Scc1(Mcd1) could, however, still be cleaved as its dependence on Cdc5 phosphoryla- tion is not absolute 74,76 .Alternatively, Rec8, but not Scc1(Mcd1), might be able to interact with proteins around centromeres that result in Rec8 being resistant to cleavage by separase. MEI-S332 and other factors. Several factors, in addition to Rec8 itself, have been identified that control the step- wise loss of cohesins from chromosomes. In budding yeast, the meiosis-specific protein Spo13,which bears no conserved motifs, is present during meiosis I, but not meiosis II (REF. 77), and functions in the maintenance of centromeric cohesion. Cells that lack SPO13 are KINETOCHORE A complex that is composed of a large number of proteins that mediate the attachment of chromosomes to microtubules. Figure 3 | The early crossover decision (ECD) model for meiotic recombination. Recombination initiates with DNA double-strand breaks (DSBs). DNA cleavage is mediated by the highly conserved sporulation protein (Spo)11 topoisomerase. Following DSB formation, the DNA is resected from its 5? end, a reaction that depends on a complex that comprises Rad50, meiotic recombination protein (Mre)11 and X-ray-sensitive protein (Xrs)2. Next, 3? single-stranded DNA tails invade the intact homologous DNA duplex. This nascent 3? interaction is unstable and it is at this step of the process that the decision is made to follow the non-crossover (NCO; left) or the crossover (CO) pathway (right). In the NCO pathway, the 3? single-stranded tail initiates DNA synthesis (shown in red) but the extended end is ejected. It then anneals with its partner and DNA synthesis is completed and followed by ligation. In the CO pathway, the nascent 3? interaction is stabilized to form a single-end invasion (SEI) intermediate. The second 3? end then invades or anneals with the displaced strand of the SEI intermediate (second-end annealing). DNA synthesis then ensues from both 3? ends and is followed by ligation to form a double Holliday junction (DHJ). The DHJ is then nicked as indicated by the arrows and resolved to form two recombinant DNA molecules. Adapted from REF. 35. Ejection of extended end Annealing of extended end DNA synthesis, ligation Second-end annealing DNA synthesis, ligation Resolution of DHJ SEI NCO CO DSB resection of 5? ends Unstable interaction with homologous chromatid DNA synthesis NCO pathway CO pathway 5? 3? 5?3? Stabilization of interaction to form an SEI intermediate � 2004 Nature Publishing Group NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | DECEMBER 2004 | 989 REVIEWS to understand how Sgo1 association with kineto- chores is regulated. Meiosis I: centromeric cohesion Some kinetochore proteins are important for defining the domain of centromeric cohesion that is protected during meiosis I (REFS 88?90).Fission yeast protein Bub1, a protein kinase with a conserved function in the spindle checkpoint (a checkpoint that monitors the attach- ment of microtubules to kinetochores; see BOX 1), is required for the retention of Rec8 at centromeres dur- ing meiosis I (REF. 91).This requirement can be explained by the failure of Sgo1 to localize to kineto- chores in the bub1? mutant 84 .In budding yeast, two kinetochore proteins, increased minichromosome loss (Iml)3 and chromosome loss (Chl)4,are required for the maintenance of centromeric cohesion in meiosis I (REF. 85).However, not all kinetochore proteins are involved in regulating centromeric cohesion 85 ,which argues that Iml3 and Chl4 have a direct role in the establishment of cohesion, rather than simply protect- ing the integrity of the kinetochore. It is also clear that Rec8 is not protected from removal solely at the centromere, but is also pro- tected on the adjacent chromatin. Cohesins are also maintained at pericentromeric heterochromatin, which is required to preserve cohesion between sister chromatids beyond meiosis I in organisms other than budding yeast (budding yeast does not have pericen- tromeric heterochromatin; FIG. 5) 92,93 .In fission yeast, the recruitment and maintenance of Rec8?Psc3 cohesin complexes to pericentromeric heterochro- matin depends on the heterochromatin-establish- ment factors Swi6 and cryptic loci regulator (Clr)4 (REF. 59) (FIG. 5).However, the retention of Rec8?Psc3 complexes at the central core of the fission yeast cen- tromere is independent of Clr4 or Swi6. This indi- cates that cohesin complexes localize to centromeres and pericentromeric regions through different mech- anisms 59 .Sgo1 is localized to the pericentromeric regions, rather than the central-core regions, so it is ideally situated to protect precisely those Rec8 com- plexes that preserve cohesion around centromeres 84 . In the fruitfly, MEI-S332 localization depends on functional centromeric chromatin but is separable from kinetochore assembly 94,95 .How can we reconcile the observations that pericentromeric heterochro- matin and bona fide kinetochore proteins are both important for the establishment of a domain where cohesins are protected from removal? Perhaps in analogy to the ability of the kinetochore to organize a large domain of cohesion around itself 96 ,the kineto- chore functions as a seed from which the protective proteins are spread throughout the pericentromeric region. Meiosis I: kinetochore co-orientation During mitosis, sister chromatids attach to microtubules from opposite poles and are segregated away from each other before cell division (FIG. 1).In mitosis and meiosis II, kinetochores of sister chromatids (sister kinetochores) during meiosis, other factors, for example, Spo13- like molecules, must contribute to the ability of Sgo1 to protect centromeric cohesion during meiosis I. Perhaps the key function of such meiosis-specific factors is to inhibit the removal of Sgo1 from kineto- chores during meiosis I, in which case it will be critical Box 1 | Chromosome segregation during mitosis The alignment of chromosomes on the metaphase spindle and their subsequent segregation at anaphase depends on the establishment and dissolution of linkages between sister chromatids. In mitosis, the cohesin complex, which consists of four proteins (structural maintenance of chromosomes (Smc)1, Smc3,subunit of the cohesin complex (Scc)1(Mcd1)/Rad21 and Scc3/Psc3 (the mammalian homologues of which are SA1/SA2)), provides this sister-chromatid cohesion 129?134 (TABLE 1).A fifth protein, precocious dissociation of sisters (Pds)5,is also essential for cohesin function 132,135?139 . Other factors function in the generation of cohesion by promoting the assembly of cohesins on the DNA. First, deposition factors load cohesins onto DNA. Subsequently, for these cohesins to be functional, other factors promote the capture of the two sister chromatids, presumably within the cohesin ring 32 . For sister chromatids to be separated at anaphase, cohesion is eliminated by the proteolytic cleavage of Scc1(Mcd1)/Rad21 by the protease separase (Esp1 in budding yeast or Cut1 in fission yeast) 140?142 .Separase is held inactive until the onset of anaphase through its binding to the inhibitor protein securin (Pds1 in budding yeast or Cut2 in fission yeast). Activation of separase occurs when the anaphase-promoting complex/cyclosome (APC/C), together with Cdc20, targets securin for destruction by the proteasome 143?145 (see figure). In mammalian cells, the bulk of cohesin is removed from chromosome arms during prophase in a separase-independent, but Aurora-B- and Polo- kinase-dependent, manner 62,63 .However, a pool of cohesins is retained on chromosomes, particularly around centromeres, which is sufficient to hold sister chromatids together. Sister chromatids are allowed to separate during anaphase only when separase-mediated cleavage of Scc1 occurs 142 . The spindle checkpoint prevents anaphase onset when kinetochores are not attached to the mitotic spindle 146 . The checkpoint components Mad2 and a BubR1-containing complex bind to the APC/C Cdc20 ,which renders the ubiquitin ligase inactive and prevents separase activation. Ub Ub Ub UbUb Securin Separase Active separase MetaphaseProphase Anaphase Polo kinase Mammals Yeast Spindle checkpoint Cohesin ring APC/C Cdc20 APC/C Cdc20 � 2004 Nature Publishing Group 990 | DECEMBER 2004 | VOLUME 5 www.nature.com/reviews/molcellbio REVIEWS functional studies indicated that it is a property of the chromosome, rather than the microtubules or the cell- cycle state, that ensures co-orientation of kinetochores in meiosis I. Paliulis and Nicklas 100 found that a homo- logue pair that was taken from grasshopper cells in meiosis I segregates in a meiosis-I-like manner when introduced onto a meiosis-II spindle by micromanipu- lation 100 .These observations imply that the kinetochore is modified in meiosis I to ensure the co-orientation of sister chromatids. Which chromosomal events are important for sister- kinetochore co-orientation? A physical linkage between homologues does not seem to be important for the monopolar attachment of sister kinetochores, at least in budding and fission yeast. Abolition of the linkages must attach to microtubules from opposite poles ? a situ- ation that is known as bi-orientation or AMPHITELIC attach- ment (FIG. 4).In meiosis I, however, sister kinetochores uniquely attach to microtubules from the same pole to ensure their co-segregation (FIGS 4,6).This is known as monopolar attachment, and sister kinetochores are said to be mono-oriented (also, more recently, referred to as co-oriented 97 ) or to have SYNTELIC attachment. The molec- ular mechanisms for this important modification in kine- tochore attachment are beginning to be understood. Cytological observations in several species indicated that sister kinetochores are fused into a single unit dur- ing meiosis I at the time of microtubule attachment, but they resolve into two distinct structures before the onset of anaphase-I chromosome segregation 98,99 .In addition, AMPHITELIC Connection of sister kinetochores to microtubules that emanate from opposite spindle pole bodies. SYNTELIC Connection of sister kinetochores to microtubules that emanate from the same spindle pole body. Figure 4 | A model for meiotic chromosome segregation. Three factors contribute to the segregation of homologues at meiosis I. First, homologues (shown in red and blue) are linked by at least one chiasma. Second, kinetochores attach to microtubules that emanate from the same pole (co-orientation; indicated by the direction of the arrows on the sister kinetochores). Third, sister chromatids are held together by cohesin rings (yellow). MEI-S332/Sgo1 (green) is shown around the centromere. During metaphase I, chromosomes are aligned ready for segregation, but separase (pink) is kept inactive by securin (purple). At the onset of anaphase I, APC/C Cdc20 (red) becomes active and ubiquitylates securin, thereby targeting it for destruction. Active separase now cleaves the Rec8 subunit of cohesin on the chromosome arms, which triggers the separation of homologues to opposite poles of the meiosis-I spindle. Centromeric Rec8 is protected from cleavage, perhaps due to the presence of MEI-S332/Sgo1. At metaphase II, kinetochores are bi-oriented and separase is once again inhibited by securin. MEI-S332/Sgo1 dissociates concomitant with, or before, the re-activation of separase at the metaphase-II?anaphase-II transition. Finally, this MEI-S332/Sgo1 dissociation leaves centromeric Rec8 free for cleavage by separase, which triggers the segregation of sister chromatids to opposite poles. Note that in fission yeast, Sgo1 dissociates from kinetochores before metaphase II and in the frog (Xenopus laevis) removal of cohesin in meiosis I seems to be separase independent 71 . Ub, ubiquitin. Ub Ub Ub UbUb APC/C Cdc20 APC/C Cdc20 Securin Separase Active separase Active separase Ub Ub Ub UbUb Kinetochores bi-oriented MEI-S332/Sgo1 MEI-S332/Sgo1 Arm cohesin lost Cohesin Kinetochores co-oriented Centromeric cohesin lost Metaphase I Anaphase I Metaphase II Anaphase II � 2004 Nature Publishing Group NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | DECEMBER 2004 | 991 REVIEWS This question has been addressed in budding and fis- sionyeast by the replacement of Rec8 with Scc1(Mcd1)/Rad21, but contrasting results were obtained. In budding yeast, Scc1(Mcd1) can adequately support co-orientation, although it cannot support the maintenance of centromeric cohesion (see above, and REF. 72). In fission yeast, however, Rec8, but not Rad21, can support sister-kinetochore co-orientation 73 .Perhaps only Rec8-containing cohesin complexes can form cohesion at centromeres during meiosis in fission yeast. Meiosis I: factors required for co-orientation The proteins that are involved in promoting co-orienta- tion during meiosis I were first identified, and are most well-characterized, in budding yeast. Mam1 (monopolar microtubule attachment during meiosis I), Csm1 (chro- mosome segregation in meiosis I) and Lrs4 (loss of rDNA silencing-4), which, together, form the ?MONOPOLIN? complex, are required for sister-kinetochore mono-ori- entation 72,103 .In the absence of MAM1, CSM1 or LRS4, sister kinetochores attach to microtubules in a bipolar manner in meiosis I (REFS 72, 103).Consistent with its role in kinetochore co-orientation, Mam1 localizes to kineto- chores during G2 and metaphase I, but dissociates from kinetochores at the onset of anaphase I (REF. 72).Unlike Mam1, Csm1 and Lrs4 are not meiosis specific as they are also present during the mitotic cell cycle, when they reside in the nucleolus 103 .During G2 and metaphase I of the meiotic cell cycle, Csm1 and Lrs4 leave the nucleo- lus and associate with kinetochores, together with Mam1. These results indicate that a monopolin complex forms at kinetochores during meiosis I and suppresses the bi- orientation of sister kinetochores. An important insight into how the monopolin com- plex is regulated came from two studies on the budding yeast Polo-like kinase Cdc5 (REF. 75,76).Depletion of Cdc5 during meiosis revealed that, in addition to its role in the removal of cohesin 76 and processing of recombination intermediates 75 , CDC5 is required for the co-orientation of sister kinetochores, which is probably due to a failure to localize the monopolin complex to kinetochores 75,76 . Cdc5 is required for both the release of Lrs4 from the nucleolus 75 and the efficient phosphorylation of Mam1 (REF. 75,76),which suggests that phosphorylation by Cdc5 regulates the function of the monopolin complex. A homologue of the monopolin component Csm1, Pcs1, has been identified in fission yeast 103 .In contrast to Csm1, Pcs1 is found at both kinetochores and in nucleoli during the mitotic cell cycle, and, surprisingly, Pcs1 is required for accurate chromosome segregation during mitosis and meiosis II, but not meiosis I. A likely expla- nation for the defect in chromosome segregation in pcs1 mutants is the MEROTELIC attachment of a single chro- matid 103 (FIG. 6).How can the opposite functions of Csm1 and Pcs1 be reconciled in terms of a common biochemical activity? An attractive hypothesis stems from the difference in the number of microtubules that attach to each kinetochore in the two yeasts 103 .In bud- ding yeast, each sister chromatid binds just a single microtubule and so, merotelic attachment cannot occur 104 .By contrast, fission yeast kinetochores (like the between homologues (in spo11? or rec12? mutants) does not significantly interfere with sister-kinetochore co-orientation 30,59,101 ,but Rec12 of fission yeast might become important for monopolar attachment in situa- tions where kinetochore orientation is unstable 102 . Sister-chromatid cohesion is important for the co-ori- entation of sister kinetochores in both budding and fission yeast. In the absence of REC8,co-orientation of sister kinetochores during meiosis I is lost and sister chromatids segregate randomly 30,56 .Does this reflect a specific requirement for the meiotic cohesins in co- orientation, or simply a need for sister chromatids to be held together by cohesion for them to co-orient? MONOPOLIN COMPLEX A protein complex that ensures the syntelic attachment of sister kinetochores during meiosis I. MEROTELIC Attachment of a single kinetochore to microtubules from both spindle-pole bodies. Figure 5 | A model for the control of pericentromeric and centromeric cohesion in fission yeast. Sister chromatids of one homologue are held together by cohesin rings (yellow). Specialized nucleosomes that contain the histone variant centromere protein-1 (Cnp1; the fission yeast orthologue of human CENP-A; orange) are present at the central-core regions. Outside the centromeric and pericentromeric regions, on the chromosome arms, nucleosomes are hypoacetylated (red), whereas the pericentromeric region is heterochromatic and nucleosomes are acetylated (blue). These heterochromatic nucleosomes attract the heterochromatin- establishment factor, Swi6. The inner centromere directs the assembly of the kinetochore, which mediates the binding of microtubules (dark green). We postulate that binding of shugoshin (Sgo1), and perhaps other cohesin protectors, to the pericentromeric region is controlled both by heterochromatin-establishment factors and bona fide kinetochore proteins. The precise location of Bub1 at the centromere is unknown. Adapted from REFS 31,59. B u b 1 Bub1 Arm Arm Pericentr omeric heter ochr omatin Pericentr omeric heter o chr omatin Central cor e Swi6 Swi6 Swi6 Swi6 Sgo1 Swi6 Swi6 Swi6 Swi6 Sgo1 Sgo1 Bub1 Bub1 Bub1 B u b 1 B u b 1 B u b 1 Sgo1 Cnp1-containing inner centromeric nucleosomes Heterochromatic/pericentromeric nucleosomes Non-pericentromeric nucleosomes (arm) Microtubule ? Sgo1 Sgo1 Sgo1 � 2004 Nature Publishing Group 992 | DECEMBER 2004 | VOLUME 5 www.nature.com/reviews/molcellbio REVIEWS Figure 6 | Kinetochore orientation in mitosis and meiosis. a | In mitosis and meiosis II, fission yeast Pcs1 prevents the merotelic attachment of kinetochores to the microtubular spindle, perhaps by ?clamping? together adjacent microtubule- binding sites on the kinetochore. Merotelic attachment (that is, the attachment of a single kinetochore to microtubules from both poles) is avoided in budding yeast as there is only one microtubule-binding site per kinetochore 104 . Unattached kinetochores trigger the activation of the spindle checkpoint, which inhibits anaphase-promoting-complex/cyclosome?Cdc20 (APC/C Cdc20 ), thereby preventing the degradation of securin and the loss of cohesin (yellow). Syntelic (or monopolar) attachments are destabilized by the Aurora-B kinase Ipl1, at least in budding yeast, which perhaps senses the lack of tension across sister kinetochores. Only when stable amphitelic (or bipolar) attachments are generated does anaphase onset occur. b | In meiosis I, sister kinetochores must be co-oriented and homologues bi-oriented. In budding yeast, the monopolin complex inhibits amphitelic attachment, perhaps by ?clamping? together microtubule-binding sites on adjacent sister kinetochores. The spindle checkpoint also functions in meiosis I and is presumably also activated in response to unattached kinetochores. There must also be a mechanism in meiosis to ensure that homologues are bi-oriented. Such a mechanism could correct homologue co-orientation by sensing the lack of tension across chiasmata and destabilize microtubule attachments on one homologue (see question mark). Note that in contrast to mitosis and meiosis II, the correct microtubule attachment at meiosis I would not generate tension across sister kinetochores. It is not known whether Ipl1 is capable of destabilizing syntelic attachments in meiosis I, but if it is, Ipl1 must somehow be prevented from doing so, perhaps by the monopolin complex. In budding yeast, the spindle-checkpoint component mitotic-arrest deficient (Mad)2 also seems to have a role in correcting kinetochore orientation during meiosis I, although another spindle-checkpoint component, Mad3, does not share this role (REFS 107,108). Unattached kinetochore Unattached kinetochore Psc1 Ipl1 Amphitelic attachment Anaphase onset Spindle checkpoint Merotelic attachment Syntelic attachment (no tension) Syntelic attachment, homologues bi-oriented Amphitelic attachment Homologues co-oriented (no tension) a b Mad2? ? Ipl1? Monopolin Anaphase onset Spindle checkpoint Direction of kinetochore orientation Kinetochore attached to microtubules from both directions Kinetochores fused by monopolin � 2004 Nature Publishing Group NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | DECEMBER 2004 | 993 REVIEWS lead to activation of the spindle checkpoint and arrest in metaphase I. Elegant experiments in grasshopper sper- matocytes support this idea 111 .However, achiasmatic mutants in budding yeast progress through both mei- otic divisions despite the absence of tension on kineto- chores 112 .Furthermore, cells that lack MAM1 orient kinetochores in an exclusively bipolar manner 72 despite the presence of chiasmata, which should provide the necessary tension to allow for at least some bivalents to bi-orient on the meiosis-I spindle. These observations indicate that, in addition to tension-sensing mecha- nisms, other controls are involved in establishing proper kinetochore?microtubule attachments during meiosis I. The meiosis-I?meiosis-II transition In mitosis, DNA replication during S phase and chro- mosome segregation in M phase alternate to maintain the ploidy of daughter cells. This alternation of S and M phases in mitosis is achieved through fluctuations in mitotic CDK activity (FIG. 2).A particular curiosity of the meiotic cell cycle is the lack of a DNA-replica- tion phase between meiosis I and meiosis II. At the meiosis-I?meiosis-II transition, conditions must be established that both trigger meiotic spindle disas- sembly (low CDK activity) and prevent the formation of pre-replicative complexes (high CDK activity). How are these two apparently opposite conditions met by the cell-cycle machinery? Insights into this question have been obtained from the yeast and frog systems. Work in frog oocytes has shown that an intermediate level of CDK activity is retained between meiosis I and meiosis II, and that this is necessary to prevent DNA replication 113,114 .Even though complete CDK inactiva- tion interferes with the meiotic cell-cycle programme, the partial inactivation of CDKs that occurs during the meiosis-I?meiosis-II transition seems not to be neces- sary for this transition in frog oocytes. When APC/C Cdc20 activity is inhibited and CDK activity remains elevated between meiosis I and meiosis II, meiosis II occurs 71 . Although this does not exclude a role for the APC/C in the meiosis-I?meiosis-II transition (perhaps in cooper- ation with an accessory factor that is different from Cdc20), it does show that the levels of CDK activity do not need to be substantially lowered. However, comple- tion of meiosis I in the frog is inhibited by injection of non-degradable cyclin B (REF. 115),which leaves open the possibility that a subtle shift in the balance between the rate of synthesis and degradation of cyclin B could regulate the meiosis-I?meiosis-II transition, as has been suggested for the mouse 116 . In budding yeast, lowering of the CDK activity dur- ing the meiosis-I?meiosis-II transition is important. Although some meiosis-II events can occur without downregulation of CDK activity between meiosis I and meiosis II, proper coordination of chromosome segre- gation is lost, with disastrous consequences 117,118 .In budding yeast, the protein phosphatase Cdc14 was found to be required, as it is in mitosis, for the down- regulation of B-type cyclins and exit from meiosis I kinetochores of most other organisms) have several microtubule-binding sites 105 , and therefore require a mechanism to ensure that all binding sites on a kineto- chore capture microtubules from the same pole to avoid merotelic attachment. It has been suggested 103 that Pcs1 provides this activity by ?clamping? together micro- tubules from the same pole at the kinetochore. An anal- ogous role for Csm1 during meiosis I can be envisioned. It is likely that both sister kinetochores bind a micro- tubule during meiosis I in budding yeast, and Csm1 might function to ?clamp? these two microtubule-bind- ing sites together. If Pcs1 is not required for meiosis I, which factors ensure the co-orientation of kinetochores in fission yeast meiosis I? Rec8 and Bub1 are two such factors 73,91 ,but other, as-yet-unknown proteins are likely to be involved because haploid cells that are engineered to undergo meiosis do not establish co-orientation, even though Rec8 is assembled onto the chromosomes 102 .Co-orientation does, however, occur in these cells if they receive mating pheromone. This indicates that mating-pheromone signalling, which is one of the events that usually precedes meiosis, triggers the expression of genes that are required for sister-kinetochore co-orientation in fission yeast. Meiosis I: allowing co-orientation During mitosis, anaphase onset does not occur until all pairs of sister chromatids have attached to the mitotic spindle in a bipolar manner; that is, they are bi-oriented (BOX 1; FIG. 6).Two factors contribute to establishing bipo- lar attachment. First, the spindle checkpoint senses the presence of unattached kinetochores and delays cell- cycle progression until all kinetochores are attached (reviewed in REF. 106;see also BOX 1). The spindle check- point also functions during meiosis I, at least in yeast, and is likely to sense attachment defects 107,108 .The second factor that contributes to bipolar attachment in mitosis in budding yeast is the Aurora-B-like protein kinase Ipl1, which senses whether kinetochores are bi-oriented (per- haps by sensing tension at the kinetochore that is exerted by the pulling force of microtubules) 109,110 .Ifkineto- chores are not bi-oriented, and therefore tension on kinetochores is absent, Ipl1 severs these faulty micro- tubule?kinetochore attachments. Unattached kineto- chores are then sensed by the spindle checkpoint (BOX 1) and anaphase onset is inhibited. In contrast to mitosis, when co-oriented kinetochores represent faulty attachments, co-oriented kinetochores are the rule during meiosis I (FIG. 6).Sister kinetochores have to be co-oriented for homologues to segregate away from each other. How does this work? At least in bud- ding yeast, the monopolin complex probably prevents kinetochores from bi-orienting, perhaps by fusing sister kinetochores by clamping together microtubule-bind- ing sites on adjacent sister kinetochores. Linkages, such as chiasmata, between homologues could create tension at kinetochores. Bivalents attaching to microtubules that emanate from the same pole would be detected due to the absence of tension at kinetochores, and such attach- ments would be severed ? perhaps by an Ipl1-medi- ated mechanism. Unattached kinetochores would then � 2004 Nature Publishing Group 994 | DECEMBER 2004 | VOLUME 5 www.nature.com/reviews/molcellbio REVIEWS (REFS 117,118).In the absence of Cdc14 or its regulator, the Cdc14 early anaphase release (FEAR) network, or in the presence of a non-degradable version of B-type cyclins, the meiosis-I spindle does not break down and meiosis-II spindles do not form 117,118 .These results indicate that CDK downregulation is critical for meio- sis-I spindle disassembly. Surprisingly, however, other meiosis-II events occur in the absence of CDK down- regulation, which leads to a meiosis-II-like segregation occurring on the meiosis-I spindle 117,118 .These observa- tions indicate that, in budding yeast, downregulation of meiotic CDKs between meiosis I and meiosis II is important to ensure that chromosome segregation is coupled to the meiotic spindle cycle 117,118 . How is residual CDK activity retained between the two meiotic divisions? Two mechanisms seem to con- tribute to this in frog oocytes: first, the partial inhibition of cyclin-B degradation upon exit from meiosis I; and second, the increased synthesis of cyclin B upon entry into meiosis II (REFS 71,119,120).Although the molecular details are not known, both processes seem to be medi- ated by the p90Rsk kinase, which functions downstream of the Mos?mitogen-activated-protein-kinase (MAPK) pathway 71,113,121 . p90Rsk is required for the partial inhibi- tion of APC/C (REF. 120).The chromokinesin Xkid also seems to have a role in the meiosis-I?meiosis-II transi- tion, which is independent of its function in metaphase chromosome alignment 122 .Furthermore, the retention of CDK activity between meiosis I and meiosis II depends on keeping two kinases, Wee1 and Myt1, inac- tive, as they phosphorylate and thereby inhibit Cdc2. Wee1 activity is inhibited because residual CDK activ- ity is sufficient to overcome the low amount of Wee1 (REFS 114,123).Myt1 is kept inactive through phosphory- lation by p90Rsk (REF. 124) and probably also by Plk1, which functions downstream of the Mos?MAPK path- way. In fission yeast, the mes1 + gene might be important for retaining CDK activity between the two meiotic divi- sions. In the absence of mes1 + ,cells complete meiosis I but fail to enter meiosis II (REF. 125).This phenotype is similar to that exhibited by budding yeast cells that lack the B-type cyclins Clb1, Clb3 and Clb4 (REF. 126,127), which raises the possibility that mes1 + somehow func- tions to prevent complete CDK inactivation during the meiosis-I?meiosis-II transition. Meiosis II The specialized meiosis-I chromosome segregation is followed by a second chromosome-segregation phase, meiosis II. How CDKs are reactivated to allow entry into meiosis II is not known, although, at least in the frog, it depends on the synthesis of new B-type cyclins 119 . Meiosis-II chromosome segregation closely resembles mitosis. Sister kinetochores are bi-oriented, which is pre- sumably due to the fact that the monopolin complex is no longer at kinetochores 72,103 .The centromeric cohesin complex, which escaped cleavage in meiosis I, resists the pulling force of the meiosis-II spindle before anaphase-II onset and so prevents the premature separation of sister chromatids (FIG. 4).At the onset of anaphase II, at least in budding yeast, separase once again becomes active and, as Box 2 | Cytostatic-factor-mediated meiotic arrests Masui and Markert first described an activity, known as cytostatic factor (CSF),that causes frog (Xenopus laevis) oocytes to arrest in metaphase II (REF. 147).CSF activity comprises at least three, possibly redundant, pathways that converge on the inhibition of the anaphase-promoting complex/cyclosome (APC/C), therefore preventing the degradation of cyclin B. The Mos?mitogen-activated-protein-kinase (MAPK) pathway is one of these pathways 120 .Mos is present from G2 until after fertilization and is required for metaphase-II arrest in mouse oocytes 148?150 . Furthermore, Mos, MAPK and p90Rsk behave like CSF in their ability to induce cell- cycle arrest when injected into mitotically dividing embryonic cells 121,151?153 . However, fruitfly (Drosophila melanogaster) Mos (DMOS) is not required for metaphase-I arrest of oocytes 154 .Activated p90Rsk phosphorylates and activates the APC/C inhibitor and spindle-checkpoint component Bub1, which inhibits APC/C activity 155 .Two other spindle-checkpoint components, mitotic-arrest deficient (Mad)1 and Mad2, are also required for Mos-mediated APC/C inhibition 156 . Interestingly, CSF arrest occurs with all kinetochores attached to the spindle, a situation in which the spindle checkpoint is normally silenced, which indicates a more general role for spindle-checkpoint components in regulating APC/C activity. The contribution of Myt1 in mediating the downstream effects of the Mos?MAPK cascade is likely to be minor. The second pathway that contributes to the inhibition of the APC/C involves cyclin- dependent kinase (Cdk)2?cyclin-E. Cyclin-E levels rise before meiosis II (REF. 157) and Cdk2?cyclin-E can inhibit the APC/C (REF. 155,158). The third pathway that mediates APC/C inhibition in metaphase II is the APC/C inhibitor early meiotic induction (Emi)1 (REF. 159).Emi1 directly binds to the APC/C activator, Cdc20 (also known as Fizzy), and inhibits it 160 .Depletion of Emi1 is sufficient to cause cyclin-B degradation and release from the metaphase-II arrest, which indicates that Emi1 is a key factor in maintaining a CSF arrest 159 . Fertilization of the frog oocyte is associated with a rise in intracellular Ca 2+ (REF. 161), which is sensed by the calmodulin-dependent kinase (CaMKII) 162 . The targets of CaMKII in triggering release from CSF-mediated arrest are not known, although both Mad1 and Emi1, but not Mos, need to be inactivated before release from the metaphase-II arrest can occur 70,159 .Components shown in blue are involved in establishing CSF arrest, and those in red need to be inactivated before release from the arrest. MEK, MAPK and ERK (extracellular signal-regulated kinase) kinase. The figure is adapted from REF. 159. Ca 2+ influx CaMKII ? Emi1 ? (?) Myt1 Cdc25 Mos MEK MAPK p90Rsk P P TY Cdc2 APC/C Cdc20 Cyclin B Cdk2 Cyclin E TY Cdc2 Cyclin B Bub1 Mad2 Mad1 Inactive meiosis-II exit Active metaphase-II arrest Oocyte � 2004 Nature Publishing Group NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | DECEMBER 2004 | 995 REVIEWS establishment of specialized interactions between chromosomes, coupled with modifications of the cell- cycle machinery. Errors in these pathways result in defective chromosome segregation, which accounts for many birth defects and the majority of miscarriages in humans. It is worth noting that, in humans, up to 10% of all conceptions are estimated to be aneuploid 128 . Most chromosome-missegregation events in human meiosis occur as a result of improper segregation of homologues during meiosis I (REF. 128).An important goal for the future is to understand how the controls that regulate this unique chromosome-segregation event are put in place. 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Cohesin component dynamics during meiotic prophase I in mammalian oocytes. Chromosome Res. 12, 197?213 (2004). 181. Revenkova, E., Eijpe, M., Heyting, C., Gross, B. & Jessberger, R. Novel meiosis-specific isoform of mammalian smc1. Mol. Cell. Biol. 21, 6984?6998 (2001). Acknowledgements We are grateful to T. Orr-Weaver and members of the Amon labora- tory for their critical reading of this manuscript. We apologize to our colleagues whose work was not discussed in this review due to space limitations. Competing interests statement The authors declare no competing financial interests. Online links DATABASES The following terms in this article are linked online to: Flybase: http://flybase.bio.indiana.edu/ MEI-S332 Saccharomyces genome database: http://www.yeastgenome.org/ Cdc5 | Cdc14 | Cdc28 | Chl4 | CLB1 | CLB3 | CLB4 | Clb5 | Clb6 | Csm1 | Emi1 | Esp1 | IME1 | IME2 | Iml3 | Ipl1 | Mam1 | MUM2 | Ndt80 | Pds5 | Rec8 | Scc1 | Scc3 | Sgo1 | Sic1 | Smc1 | Smc3 | Spo11 | Spo13 | Sum1 | Swe1 S. pombe gene database: http://www.genedb.org/genedb/pombe/index.jsp Bub1 | Clr4 | Cnp1 | Mei2 | Mei3 | meiRNA | mes1 + | Pat1 | Pcs1 | Psc3 | Rad21 | Rec11 | Rec12 | Sgo2 | Swi6 Access to this links box is available online. ERRATUM MEIOSIS: CELLuniF6BACYCLE CONTROLS SHUFFLE AND DEAL Ad�le L. Marston & Angelika Amon Nature Reviews Molecular Cell Biology 5, 983?997 (2004); doi:10.1038/nrm1526 On page 984 of this article, in Figure 1b, the homologous chromosomes were incorrectly shaded at the transition between meiosis I and meiosis II. A corrected version of the figure is shown below. The online versions of this article have been corrected. G1 S Meiosis I G2 Meiosis II Diploid Haploid Homologues segregate Sister chromatids segregate Chiasma b Homologues Sister chromatids www.nature.com/reviews/molcellbio ERRATUM "
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