Stephen P Jackson

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..Our improving understanding of DNA-damage responses is providing new avenues for disease management...

..Finally, I explain how our increasing knowledge of the DDR is suggesting new avenues for treating cancer and provide an example of a DDR-inhibitory drug that is showing promise in clinical trials...

..These findings provide a molecular explanation for the MDC1-MRN interaction and yield insights into how MDC1 coordinates the focal assembly and activation of several DDR factors in response to DNA damage...

..Thus, in response to DSBs, ATR activation is regulated by ATM in a cell-cycle dependent manner...

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..These results provide new insights into how the chromatin remodelling complex NuRD contributes to maintaining genome stability...

..These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination...

..These findings establish hnRNP K as a new HDM2 target and show that, by serving as a cofactor for p53, hnRNP K plays key roles in coordinating transcriptional responses to DNA damage...

..Thus, CDK-mediated NBS1 phosphorylation defines a molecular switch that controls the choice of repair mode for DSBs...

..These findings therefore provide a mechanistic basis for cell-cycle control of DSB repair and highlight the importance of regulating DSB resection...

..Our data are most consistent with head-to-head interactions in a 2:2:1 XRCC4:XLF:Ligase IV complex...

..These results suggest that CDK-mediated control of resection in human cells operates by mechanisms similar to those recently established in yeast...

..Taken together, these data indicate that Nhp6A/B and Hmgb1 protect DNA from damaging agents and thus guard against the generation of genomic aberrations...

..These findings further clarify how SIRT6 promotes genome stability...

..Thus, MDC1/NFBD1 appears to be a key regulator of the DNA damage response in mammalian cells...

..Finally, we present data suggesting that induction of a primary DDR in mitosis is important because transient inactivation of ATM and DNA-PK renders mitotic cells hypersensitive to DSB-inducing agents...

..Collectively, these data establish evolutionarily conserved roles for the BLM and Sgs1 helicases in DSB processing, signaling, and repair...

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..Thus, binding of MDC1/NFBD1 to gammaH2AX plays a central role in the mammalian response to DNA damage...

..Finally, we observe weak gammaH2AX signals at telomeres of proliferating cells, but not in hTERT immortalised cells, suggesting that low telomerase activity leads to telomere uncapping and senescence in proliferating primary cells...

..We discuss these and other recent findings and suggest how these novel data collectively contribute to our understanding of mitosis and how cells deal with DNA damage during this crucial cell cycle stage...

..Chk1-mediated protection of replication forks from Mus81/Eme1 even under otherwise unchallenged conditions is therefore vital to prevent uncontrolled fork collapse and ensure proper S-phase progression in human cells...

..Despite its paramount importance, how Chk1 controls these functions remains unclear, mainly because very few Chk1 substrates have hitherto been identified...

..The structure reveals a novel mode of protein recognition by a tandem BRCT repeat, and in addition provides a molecular basis for a human LIG4 syndrome clinical condition...

..Taken together with other data, these findings indicate that the Yku80p-Sir4p interaction plays a vital role in the assembly of telomeric heterochromatin...

..These findings indicate that constitutive Tudor domain-mediated and damage-specific BRCT domain-phospho-H2A-dependent interactions of Rad9 with chromatin cooperate to establish G1 checkpoint arrest...

..Within these pathways, the effector kinase Chk1 plays a central role in mediating cell-cycle arrest in response to DNA damage, and it does so by phosphorylating key cell-cycle regulators...

..RNF4 thus operates as a DSB response factor at the crossroads between the SUMO and ubiquitin systems...

..Our unbiased approach to define genomic sites of action for a drug establishes a framework for discovering functional DNA-drug interactions...

..Collectively, these results provide insights into how mammalian cells respond to DSBs...

..Collectively, our data indicate that though most histone modifications do not change appreciably after genotoxic stress, H3K9Ac and H3K56Ac are reduced in response to DNA damage in human cells...

..These findings thus identify PIAS1 and PIAS4 as components of the DDR and reveal how protein recruitment to DSB sites is controlled by coordinated SUMOylation and ubiquitylation...

..These data reveal structural and functional parallels between bacteriophage Gam and eukaryotic Ku and suggest that their functions have been evolutionarily conserved...

..These findings invoke a model wherein incomplete DNA synthesis during S phase leads to a DNA damage response and formation of 53BP1-OPT domains in the subsequent G1...

..We conclude that KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase...

..Thus, phosphorylation of H2A at DNA damage sites creates a mark recognized by different chromatin modifiers. This interaction leads to stepwise chromatin reconfiguration, allowing efficient DNA repair...

..These data establish Rtt109p as a member of a new class of histone acetyltransferases and show that its actions are critical for cell survival in the presence of DNA damage during S phase...

..The molecular defect that underlies these phenotypes has long been thought to be related to a DNA repair deficiency. However, recent studies have uncovered functions for the Mre11 complex in checkpoint signalling and DNA replication...

..We demonstrate that DNA repair through BER represents a core component of genome-wide DNA demethylation in vivo and provides a mechanistic link to the extensive chromatin remodeling in developing PGCs...

..These findings reveal that MDC1-mediated focus formation by the MRE11 complex at sites of DNA damage is crucial for the efficient activation of the intra-S-phase checkpoint...

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..Taken together, these results define a role for the Sin3p/Rpd3p complex in the modulation of DNA repair...

..Furthermore, the genomic instability exhibited by BRCA1-deficient cells might result from a failure to efficiently exclude 53BP1 from such regions during S phase...

..Here, we present a high-throughput flow-cytometry method that allows the use of RPA staining to measure cell proliferation and DNA-damage repair by HR in an unprecedented, unbiased and quantitative manner...

..We propose that a major mechanism by which p53 maintains genome stability is the prevention of DSB accumulation at long-lived ssDNA regions in stalled-replication forks...

..We consider the identities of the key DNA damage response factors involved in senescence and discuss a model for the molecular events occurring in pre-senescent cells that ultimately lead to a permanent cell cycle arrest phenotype...

..XLF thus constitutes a novel core component of the mammalian NHEJ apparatus...

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..These data suggest a model in which Mec1-mediated phosphorylation of Rad51 Ser 192 in response to DNA damage controls Rad51 activity and DNA repair by homologous recombination...

..We also discuss the potential diagnostic, prognostic and therapeutic implications of chromothripsis in cancer...

..The availability of the complete genome sequence of Saccharomyces cerevissiae has greatly facilitated the discovery of new genes important for DNA repair...

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..These data provide a paradigm for how Sir2 family proteins influence transcription and suggest that modulation of chromatin structure by acetylation arose before the divergence of the archaeal and eukaryotic lineages...

..These results further our understanding of the role of DNA resection in repair of replication-born DSBs revealing unanticipated differences between these events and repair of enzymatically induced DSBs...

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..Finally, we show that Hho1p is inhibitory to the recombination-dependent mechanism of telomere maintenance. The role of linker histones in genome stability, aging, and tumorigenesis is discussed...

..We review these regulatory mechanisms and discuss their biological significance to the DDR...

..Instead, the mechanism of attenuation of retroviral infection by RAD52 appears to be based upon competition between the RAD52 protein and active integration complexes for the retroviral cDNA genome...

..In contrast, it is still unclear how primary DNA damage is detected and how this interfaces with signal transduction and DNA repair proteins...

..Together, these findings reveal evolutionary and functional conservation of Dma proteins, and suggest that RNF8 maintains genome stability through independent, yet analogous, nuclear and cytoplasmic ubiquitylation activities...

..An increased knowledge of DSB repair and of other DNA DSB responses may therefore provide opportunities for developing more effective treatments for cancer...