Articles in 2012

Repair of double-strand breaks by homologous recombination is thought to involve the movement of damaged chromosomes to facilitate pairing of homologues. Gasser and colleagues have now followed the movement of damaged loci in haploid yeast using time-lapse microscopy, revealing the dynamics of damage-induced movement and the requirement for recombination proteins in this process.

Clathrin-mediated endocytosis requires the coordinated spatial and temporal recruitment of adaptor, sorting and cargo proteins. Traub and colleagues investigate this process during zebrafish development and report that the AP-2 adaptor protein complex has a key, early role in clathrin-coated bud formation. Fcho1/2, though necessary for proper development, seems to act downstream of AP-2.

D’Adda di Fagagna and colleagues observe that, after genotoxic treatment of cells and mice, unrepaired DNA-damage foci and DNA-damage signalling persist at telomeres. They show that introducing the telomeric protein TRF2 near a double-strand break elsewhere on the chromosomes prevents repair. Unrepaired foci are also observed at telomeres of ageing animals, suggesting a role for TRF2 in senescence establishment.

Yang and colleagues delineate a pathway that controls cell migration in 3D environments following Twist1-mediated epithelial-to-mesenchymal transition. They show that Twist1 represses the let-7i microRNA, leading to upregulation of the RAC1-activating factors NEDD9 and DOCK3, and inducing mesenchymal-mode motility and tumour invasion in vivo.

The SCF ubiquitin ligase subunit Fbxw7 is a tumour suppressor that is mutated in many cancers. Pagano and colleagues now show that in multiple myeloma, Fbxw7α instead functions as a pro-survival factor by activating the NF-κB pathway through the ubiquitin-mediated degradation of p100, an NF-κB pathway inhibitor.

Cellular senescence is partly caused by RB1/E2F-mediated repression of proliferation genes. Bischof and colleagues now demonstrate that RB1 interacts with the microRNA effector AGO2, and that AGO2 and the microRNA let-7 are needed for chromatin remodelling and repression of E2F-target loci.

Formation and fission of large membrane-bound carriers at the Golgi requires coordinated action by a myriad of proteins, including PI(4)KIIIβ and CtBP1-S/BARS. Corda and colleagues reveal that the scaffold protein 14-3-3γ bridges BARS to PI(4)KIIIβ, thus mechanistically linking carrier budding and tubulation with tubule fission.

GGA proteins and the AP-1 complex are clathrin adaptors that regulate trans-Golgi network (TGN)-to-endosome traffic. Payne and colleagues show that these adaptors are recruited to the TGN in sequential waves, and reveal that phosphatidylinositol-4-monophosphate (PtdIns(4)P) coordinates the temporal assembly of these adaptors.

Chronic lymphocytic leukaemia cells depend on glutathione to counteract their high reactive oxygen species (ROS) levels. However, their ability to synthesize this antioxidant is compromised by inefficient cystine uptake. Huang and colleagues now show that bone marrow stromal cells promote leukaemia cell survival by metabolizing cystine to cysteine and releasing it into the microenvironment to be taken up by leukaemia cells.

Dimmeler and colleagues show that the atheroprotective transcription factor KLF2 activates expression of the microRNAs miR-143/145 in endothelial cells. miR-143/145 are subsequently enriched in secreted microvesicles and taken up by smooth muscle cells to elicit anti-atherogenic responses.

Verma and colleagues develop a mouse model to study the role of the NF-κB pathway in lung cancer. They show that depletion of IKK2, a kinase needed for NF-κB activation, inhibits the induction of Timp1. This suppresses the Timp-1-mediated activation of Erk, resulting in decreased tumour-cell proliferation and prolonged survival.

Cyclin B is targeted for proteasome-mediated degradation by the E3 ligase APC/C, which is thought to generate polyubiquitin chains for the degradation of mitotic substrates. King and colleagues now demonstrate in Xenopus laevis extracts that multiple monoubiquitylation events are sufficient to target cyclin B1 for degradation.

Asymmetric Notch signalling is important in many developmental contexts, including the division of fly sensory organ precursor (SOP) cells. Here, Notch is inactivated by Numb in the resulting pIIb daughter cell while remaining active in pIIa to direct cell fate. Using live imaging, Schweisguth and colleagues reveal that Numb and Sanpodo act together, modulating Notch trafficking to deplete it on the pIIb side of the SOP cytokinetic furrow.

Several specialized cell types assemble hundreds of motile cilia to accomplish their function. Kintner and colleagues identify the coiled-coil protein multicilin as an essential regulator of multicilia formation in Xenopus skin and the mammalian kidney. Their data indicate that multicilin activates the transcription of genes required for multicilia formation, including the transcription factor Foxj1.