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| Open AccessThe splicing factor XAB2 interacts with ERCC1-XPF and XPG for R-loop processing
XPA-binding protein (XAB)-2 is the human homologue of the yeast pre-mRNA splicing factor Syf1. Here the authors use an in vivo biotinylation tagging approach to show XAB2’s role in DNA repair, RNA splicing and transcription during mammalian development.
- Evi Goulielmaki
- , Maria Tsekrekou
- & George A. Garinis
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Article
| Open AccessCornelia de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect
Cornelia de Lange syndrome is a developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The authors, here, by analysing previously identified mutations in BRD4 associated with the disease, reveal that a BRD4 mutation affects DNA damage signalling, and perturbs regulation of DNA repair in mutant cells.
- Gabrielle Olley
- , Madapura M. Pradeepa
- & Charlene Boumendil
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Article
| Open AccessBi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening
Minichromosome maintenance protein 10 (MCM10) is critical for eukaryotic DNA replication. Here, by modelling MCM10 variants in human cell lines, the authors reveal a mechanism of MCM10-associated disease, finding that loss of MCM10 function constrains telomerase activity.
- Ryan M. Baxley
- , Wendy Leung
- & Anja-Katrin Bielinsky
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Article
| Open AccessPrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts
Bulky DNA adducts are important replication-blocking lesions. Here the authors reveal that homologous recombination at bulky adducts in mammalian cells involves post-replicative gap repair in a PrimPol dependent manner.
- Ann Liza Piberger
- , Akhil Bowry
- & Eva Petermann
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Article
| Open AccessThe nuclear pore primes recombination-dependent DNA synthesis at arrested forks by promoting SUMO removal
In yeast, collapsed forks shift to the nuclear periphery to associate with two distinct perinuclear anchorage sites such as the nuclear pore complex. Here, the authors reveal the mechanisms engaged at nuclear pore complex facilitating fork integrity and restart via SUMO regulation.
- Karol Kramarz
- , Kamila Schirmeisen
- & Sarah A. E. Lambert
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Article
| Open AccessUbiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair
DNA damage sensors DDB2 and XPC are fundamental factors to initiate global genome nucleotide excision repair and protect DNA from mutagenesis. Here the authors reveal that ubiquitin and TFIIH-stimulated DDB2 dissociation promotes DNA damage handover to XPC in nucleotide excision repair.
- Cristina Ribeiro-Silva
- , Mariangela Sabatella
- & Hannes Lans
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Article
| Open AccessFunctional regulation of an ancestral RAG transposon ProtoRAG by a trans-acting factor YY1 in lancelet
Lancelet expresses an ancestral RAG transposon, ProtoRAG, which predates human RAGgenes that are responsible for V(D)J recombination and adaptive immunity repertoire generation. Here the authors show that ProtoRAG is functionally regulated by a trans-acting factor, bbYY1, for tuning transposon activity and maintaining genome stability.
- Song Liu
- , Shaochun Yuan
- & Anlong Xu
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Article
| Open AccessFastClone is a probabilistic tool for deconvoluting tumor heterogeneity in bulk-sequencing samples
Multiple algorithms exist for predicting heterogeneity and clonal architecture from the bulk sequencing of tumor tissue. Here, the authors report on an algorithm, FastClone, which was developed from a DREAM challenge and show that FastClone can accurately predict clonality in simulated data and data from colon cancer.
- Yao Xiao
- , Xueqing Wang
- & Yuanfang Guan
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Article
| Open AccessThe Rad53CHK1/CHK2-Spt21NPAT and Tel1ATM axes couple glucose tolerance to histone dosage and subtelomeric silencing
The relationship between DNA damage response (DDR) and regulation of the tolerance to glucose restriction is currently unclear. Here the authors reveal that maintaining a physiological level of histones by Rad53-Spt21 is necessary for glucose tolerance via multiple parallel pathways, including derepression of subtelomeric genes and acetyl-coA regulation by histone acetylation.
- Christopher Bruhn
- , Arta Ajazi
- & Marco Foiani
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Article
| Open AccessEthanol exposure increases mutation rate through error-prone polymerases
Whereas the toxic effects of ethanol are well-documented, the underlying mechanism is obscure. This study uses the eukaryotic model S. cerevisiae to reveal how exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate.
- Karin Voordeckers
- , Camilla Colding
- & Kevin J. Verstrepen
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Article
| Open AccessBRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining
Cancer mutational signatures have been associated with defects in genome maintenance pathways. Here the authors, by using a worm germline mutagenesis model defective of human orthologue BRCA-1, identify polymerase theta-mediated end-joining (TMEJ) as causing the BRCAness mutational signature.
- J. A. Kamp
- , R. van Schendel
- & M. Tijsterman
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Article
| Open AccessRad9/53BP1 promotes DNA repair via crossover recombination by limiting the Sgs1 and Mph1 helicases
In budding yeast, the 53BP1 ortholog Rad9 limits the resection nucleolytic processing of DNA double strand breaks. Here the authors reveal that Rad9 promotes long tract gene conversions, BIR and CO, during the HR repair of a DSB via modulation of Sgs1 and Mph1 helicases.
- Matteo Ferrari
- , Chetan C. Rawal
- & Achille Pellicioli
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Article
| Open AccessMCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage
Homologous recombination (HR) is an essential DNA repair pathway for genomic stability. Here the authors show that C17orf53/MCM8IP, an OB-fold containing protein, promotes HR through direct binding and activation of the MCM8-9 helicase complex.
- Jen-Wei Huang
- , Ananya Acharya
- & Alberto Ciccia
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Article
| Open AccessStability and nuclear localization of yeast telomerase depend on protein components of RNase P/MRP
Pop1 and 6 are subunits of RNase P and RNase MRP, which process ribosomal and tRNAs. The authors show that when Pop1 and 6 are impaired, the telomerase subunit Est1 binds telomerase RNA at normal levels, but the binding is unstable. As a result, nuclear import of the telomerase holoenzyme is inhibited.
- P. Daniela Garcia
- , Robert W. Leach
- & Virginia A. Zakian
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Article
| Open AccessSynthetic hybrids of six yeast species
Many industrial organisms are the result of recent or ancient allopolypoidy events. Here the authors iteratively combine the genomes of six yeast species to generate a viable hybrid.
- David Peris
- , William G. Alexander
- & Chris Todd Hittinger
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Article
| Open AccessNitrogen starvation reveals the mitotic potential of mutants in the S/MAPK pathways
Nitrogen-starved fission yeast cells survive for weeks without dividing. Here, the authors show that some of these surviving cells accumulate mutations in the stress- and mitogen-activated protein kinase pathways and outcompete their parental cells, which provide nutrients for the mutant cells.
- Rostyslav Makarenko
- , Claire Denis
- & Benoît Arcangioli
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Article
| Open AccessEndogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
The ATM kinase is a key regulator of the DNA damage response to double-strand breaks (DSBs) and its homozygous loss in patients predisposes to lymphoid malignancies. Here, the authors develop a Tdp2−/− Atm−/− double-deficient mouse model to uncover topoisomerase II-induced DSBs as significant drivers of the genomic rearrangements that underpin these tumours.
- Alejandro Álvarez-Quilón
- , José Terrón-Bautista
- & Felipe Cortés-Ledesma
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Article
| Open AccessDNA repair by Rad52 liquid droplets
Genome dynamics allow cells to repair DNA double-strand breaks (DSBs), which are highly toxic DNA lesions. Here the authors reveal that in S. cerevisiae, Rad52 DNA repair proteins assemble in liquid droplets that work with dynamic nuclear microtubules to relocalize lesions to the nuclear periphery for repair.
- Roxanne Oshidari
- , Richard Huang
- & Karim Mekhail
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Article
| Open AccessMutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice
Mutational signatures induced by ionising radiation remain largely unexplored. Here in TP53 mutant mice, the authors characterise the genomic landscape of tumours induced by high- and low-energy radiation.
- Yun Rose Li
- , Kyle D. Halliwill
- & Allan Balmain
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Article
| Open AccessTissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage
DNA damage is associated with metabolic disorders, but the mechanism in unclear. Here, the authors show that persistent DNA damage induced by lack of the endonuclease XPF-ERCC1 triggers extracellular vesicle biogenesis in tissue infiltrating macrophages, and that vesicle uptake stimulates glucose uptake in recipient cells, leading to increased inflammation.
- Evi Goulielmaki
- , Anna Ioannidou
- & George A. Garinis
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Article
| Open AccessRpd3L and Hda1 histone deacetylases facilitate repair of broken forks by promoting sister chromatid cohesion
Double strand breaks (DSBs) are preferentially repaired by sister-chromatid recombination (SCR) to maintain genome stability. Here, the authors reveal a role for histone deacetylate (HDAC) complexes favouring the repair of replication related DSBs by facilitating cohesin loading.
- Pedro Ortega
- , Belén Gómez-González
- & Andrés Aguilera
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Article
| Open AccessIntronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2
Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”
- Mark A. Corbett
- , Thessa Kroes
- & Jozef Gecz
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Article
| Open AccessUnstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
- Rahel T. Florian
- , Florian Kraft
- & Christel Depienne
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Article
| Open AccessTetraploidy causes chromosomal instability in acentriolar mouse embryos
During cell division, tetraploidy can drive chromosomal instability (CIN) via supernumerary centrosomes, but it is unclear if this is the only route to CIN. Here the authors show that, in early mouse embryos, tetraploidy can drive chromosomal instability by altering microtubule dynamics and attachment.
- Lia Mara Gomes Paim
- & Greg FitzHarris
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Article
| Open AccessMRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription–replication conflicts
Accumulations of R-loops can lead to genome instability. Here the authors reveal a role for the MRN complex in suppressing R-loops and associated DNA damage at transcription–replication conflicts.
- Emily Yun-Chia Chang
- , Shuhe Tsai
- & Peter C. Stirling
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Article
| Open AccessPolarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity
Many developing tissues require Par-driven polarization, but its role in mammalian tissue maintenance is unclear. Here, the authors show that in mouse epidermis, Par3 governs tissue homeostasis not via orientation of cell division but by coupling cell mechanics with mitotic accuracy and genome integrity.
- Martim Dias Gomes
- , Soriba Letzian
- & Sandra Iden
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Article
| Open AccessqDSB-Seq is a general method for genome-wide quantification of DNA double-strand breaks using sequencing
Measuring relative frequencies of DNA double-strand breaks between loci does not provide the full physiological relevance of those breaks. Here Rowicka and colleagues present qDSB-Seq method which uses spike-in double-strand breaks induced by a restriction enzyme to accurately quantify DNA damage.
- Yingjie Zhu
- , Anna Biernacka
- & Maga Rowicka
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Article
| Open AccessDefective homologous recombination DNA repair as therapeutic target in advanced chordoma
Chordomas are rare bone tumors with limited therapeutic options. Here, the authors identify molecular alterations associated with defective homologous recombination DNA repair in advanced chordomas and report prolonged response in a patient treated with a PARP inhibitor, which later acquired resistance due to a newly gained PARP1 mutation.
- Stefan Gröschel
- , Daniel Hübschmann
- & Stefan Fröhling
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Article
| Open AccessRad52 prevents excessive replication fork reversal and protects from nascent strand degradation
Stabilisation of stalled replication forks prevents excessive fork reversal and genome instability. Here authors reveal a RAD52-dependent replication fork protection mechanism.
- Eva Malacaria
- , Giusj Monia Pugliese
- & Pietro Pichierri
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Article
| Open AccessSFPQ and NONO suppress RNA:DNA-hybrid-related telomere instability
LncRNA TERRA forms RNA-DNA hybrids at telomere sites leading to telomere instability. Here the authors identify the RNA interacting factors NONO and SFPQ as proteins that interact with TERRA and telomere chromatin and reveal putative roles for these factors in telomere integry maintenance by interfering with RNA:DNA hybrid formation.
- Eleonora Petti
- , Valentina Buemi
- & Stefan Schoeftner
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Article
| Open AccessA recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme
Somatic alterations in the exonuclease domain of DNA polymerase ɛ have been linked to the development of highly mutated cancers. Here, the authors report that a major consequence of the most common cancer-associated Polɛ variant is a dramatically increased DNA polymerase activity.
- Xuanxuan Xing
- , Daniel P. Kane
- & Polina V. Shcherbakova
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Review Article
| Open AccessThe dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA
Centromeres are the chromosomal domains that regulate assembly of the components required for chromosome separation. Here the authors review how centromeres are a potential source of genome instability and link centromere aberrations and rearrangements to human diseases such as cancer.
- V. Barra
- & D. Fachinetti
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Article
| Open AccessThe Swr1 chromatin-remodeling complex prevents genome instability induced by replication fork progression defects
SWR-C and its substrate the histone variant Htz1 are considered important for genome maintenance. Here the authors reveal that SWR-C/Htz1 plays a critical role during replication stress caused by absence of the replication fork progression proteins Mrc1/Tof1/Csm3.
- Anjana Srivatsan
- , Bin-Zhong Li
- & Richard D. Kolodner
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Article
| Open AccessNuclear microtubule filaments mediate non-linear directional motion of chromatin and promote DNA repair
Following DNA damage, different processes come to action to aid repair. The authors here find that microtubule filaments within the cell nucleus capture and non-randomly mobilize damaged chromatin to mediate DNA repair.
- Roxanne Oshidari
- , Jonathan Strecker
- & Karim Mekhail
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Article
| Open AccessThe mitochondrial DNA polymerase gamma degrades linear DNA fragments precluding the formation of deletions
Mitochondrial DNA fragments are rapidly degraded when double strand breaks occur. Here the authors reveal that the exonuclease activity of polymerase gamma is important for efficient degradation of these fragments and to avoid formation of large deletions.
- Nadee Nissanka
- , Sandra R. Bacman
- & Carlos T. Moraes
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Article
| Open AccessDistinct roles of XPF-ERCC1 and Rad1-Rad10-Saw1 in replication-coupled and uncoupled inter-strand crosslink repair
The yeast Rad1–Rad10 complex has multiple roles in DNA damage repair. Here the authors uncover mutants that uncouple the roles in UV excision repair and non-NER functions.
- Ja-Hwan Seol
- , Cory Holland
- & Sang Eun Lee
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Article
| Open AccessValidating the concept of mutational signatures with isogenic cell models
As cells evolve towards malignancy, somatic mutations arise from defects in DNA damage and repair processes which are each associated with individual mutation signatures. Here the authors show it is possible to recreate cancer mutational signatures in vitro using gene editing experiments in an isogenic human-cell system.
- Xueqing Zou
- , Michel Owusu
- & Serena Nik-Zainal
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Article
| Open AccessTargeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome
Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.
- Gabriel Balmus
- , Delphine Larrieu
- & Stephen P. Jackson
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Article
| Open AccessCircular DNA elements of chromosomal origin are common in healthy human somatic tissue
Somatic cells can accumulate structural variations such as deletions. Here, Møller et al. show that normal human cells generate large extrachromosomal circular DNAs (eccDNAs), most likely the products of excised DNA, that can be transcriptionally active and, thus, may have phenotypic consequences.
- Henrik Devitt Møller
- , Marghoob Mohiyuddin
- & Birgitte Regenberg
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Article
| Open AccessDecapping protein EDC4 regulates DNA repair and phenocopies BRCA1
Mutations in BRCA1 are associated with an increased risk of breast and ovarian cancer. Here the authors show that EDC4, a component of P-bodies, is a member of the BRCA1 complex with roles in stimulating end resection at breaks.
- Gonzalo Hernández
- , María José Ramírez
- & Jordi Surrallés
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Article
| Open AccessBreak-induced replication promotes formation of lethal joint molecules dissolved by Srs2
Break-induced replication (BIR) is a double-strand break repair pathway that can lead to genomic instability. Here the authors show that the absence of Srs2 helicase during BIR leads to uncontrolled binding of Rad51 to single-stranded DNA, which promotes the formation of toxic intermediates that need to be resolved by Mus81 or Yen1.
- Rajula Elango
- , Ziwei Sheng
- & Anna Malkova
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Article
| Open AccessUbiquitin-specific protease 21 stabilizes BRCA2 to control DNA repair and tumor growth
BRCA2 is essential for the repair of DNA damage; therefore, defects in BRCA2 are associated with tumorigenesis but also with increased susceptibility to genotoxic stress. Here the authors show that USP21 regulates the ability of tumor cells to repair damaged DNA by regulating BRCA2 stability.
- Jinping Liu
- , Alex Kruswick
- & Philipp Oberdoerffer
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Article
| Open AccessInactivation of Pol θ and C-NHEJ eliminates off-target integration of exogenous DNA
Random off-target integration events can impair precise gene targeting and poses a safety risk for gene therapy. Here the authors show that repression of polymerase θ and classical non-homologous recombination eliminates random integration.
- Alex N. Zelensky
- , Joost Schimmel
- & Marcel Tijsterman
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Article
| Open AccessPhosphate steering by Flap Endonuclease 1 promotes 5′-flap specificity and incision to prevent genome instability
Flap Endonuclease 1 is a DNA replication and repair enzyme indispensable for maintaining genomic stability. Here the authors provide mechanistic details on how FEN1 selects for 5′-flaps and promotes catalysis to avoid large-scale repeat expansion by a process termed ‘phosphate steering’.
- Susan E. Tsutakawa
- , Mark J. Thompson
- & John A. Tainer
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Article
| Open AccessPAXX promotes KU accumulation at DNA breaks and is essential for end-joining in XLF-deficient mice
Non-homologous end-joining is the key pathway for repairing double-stranded DNA breaks in mammalian cells. Here the authors show that PAXX promotes the accumulation of KU at DNA breaks and is essential for end-joining in cells lacking XLF.
- Xiangyu Liu
- , Zhengping Shao
- & Shan Zha
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Article
| Open AccessContracting CAG/CTG repeats using the CRISPR-Cas9 nickase
The expansion of trinucleotide repeats has been linked to several neurodegenerative disorders. Here, the authors show that the CRISPR-Cas9 nuclease induces both expansions and contractions of the repeat region, whereas the nickase leads predominantly to contractions.
- Cinzia Cinesi
- , Lorène Aeschbach
- & Vincent Dion
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Article
| Open AccessTelomeric RNAs are essential to maintain telomeres
The telomeric long-non coding RNA, TERRA, has been proposed in the past to modulate different telomeric functions based on in vitrostudies. Here the authors show, using a genetic deletion approach, that TERRA is transcribed from the 20q subtelomere and that it is essential for telomere maintenance.
- Juan José Montero
- , Isabel López de Silanes
- & Maria A. Blasco
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Article
| Open AccessA genetic network that suppresses genome rearrangements in Saccharomyces cerevisiae and contains defects in cancers
Here, Richard Kolodner and colleagues use assays in Saccharomyces cerevisiaeto identify 182 genetic modifiers of gross chromosomal rearrangements (GCRs). They also compared these Genome Instability Suppressing (GIS) genes and pathways in human cancer genome, and found many ovarian and colorectal cancer cases have alterations to GIS pathways.
- Christopher D. Putnam
- , Anjana Srivatsan
- & Richard D. Kolodner
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Article
| Open AccessPhosphorylation of EB2 by Aurora B and CDK1 ensures mitotic progression and genome stability
Temporal regulation of microtubule dynamics in mitosis can be achieved by phosphorylation of microtubule plus-end proteins. Here, the authors show that Aurora B and CDK1 phosphorylate EB2, which changes microtubule binding affinity and controls kinetochore microtubule dynamics and genome stability.
- Makoto Iimori
- , Sugiko Watanabe
- & Yoshihiko Maehara