M Jasin

..A fluorescence-based reporter is first gene targeted to the Hprt locus in a quantifiable way. A homing endonuclease expression vector is then introduced to generate a double-strand break, the repair of which is also quantifiable...

..Thus, our results demonstrate that DNA ligase I-deficiency reduces recombinational repair of DNA double-strand breaks...

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..This review summarizes those studies and discusses how disruption of homologous recombination pathways can create genetic instability...

..We propose that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and, possibly, tumorigenesis, through lack of repair or misrepair of DNA damage...

..Neither sister-chromatid exchange nor gene-targeting frequencies show a dependence on these NHEJ proteins. A Ku-modulated two-ended versus one-ended chromosome break model is presented to explain these results...

..Our results also support the view that mammalian checkpoint responses to meiotic recombination and/or synapsis defects are sexually dimorphic...

..We conclude that the inability to properly repair strand breaks by homology-directed repair gives rise to defects in chromosome maintenance that promote genetic instability and, it is likely, tumorigenesis...

..In cells with MMR defects, therefore, aberrant recombinational repair may be an additional mechanism that contributes to genomic instability and possibly tumorigenesis...

..Although definitive proof has yet to be obtained, the current literature is highly suggestive of such a link...

..To date, four mammalian proteins have been demonstrated conclusively to be involved in DSB repair by homologous recombination: Rad54, XRCC2, XRCC3 and BRCA1. This paper summarizes results from a number of recent studies...

..These results may have implications for instability observed at naturally occurring palindromic or quasipalindromic sequences...

..These results establish that XRCC3-mediated homologous recombination can reverse DNA damage that would otherwise be mutagenic or lethal...

..The analysis of translocation breakpoints in a number of cancers and the development of model translocation systems are beginning to shed light on specific DSB repair pathway(s) responsible for the improper repair of broken chromosomes...

..Thus, the use of rare-cutting endonucleases and the co-opting of cellular repair mechanisms might provide scientists with another tool for engineering changes into genomes...

..Manifestation of some of these disease phenotypes, namely tumorigenesis, may require additional checkpoint deficiencies...

..Taken together, these results strongly suggest that this gene encodes the functional homolog of yeast Spo11p, which in turn suggests that the mechanism of meiotic recombination initiation is conserved between yeast and mammals...

..The repair defect in XRCC2 mutant cells appears to be restricted to recombinational repair because NHEJ is normal. We conclude that XRCC2 is involved in the repair of DNA double-strand breaks by homologous recombination...

..BLM-deficient mouse and human cells suppress homeologous recombination to a similar extent as wild-type cells, unlike Sgs1-deficient Saccharomyces cerevisiae...

..These data identify the Fanca protein as an integral component in the early step of HDR of DSBs and thereby minimizing the genomic instability...

..We conclude that Fen-1 eliminates heterologous sequences at DNA damage site and facilitates DNA repair by HR...

..Thus, despite equivalent stages of spermatocyte elimination, different recombination-defective mutants manifest distinct responses, providing insight into surveillance mechanisms in male meiosis...

..Interestingly, in a direct comparison, the spectrum of translocation breakpoint junctions differed from junctions derived from repair at a single chromosomal break, providing mechanistic insight into translocation formation...

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..Thus, RAG-generated DSBs are typically repaired by the NHEJ pathway in ES cells, but in the absence of NHEJ components, a substantial fraction of breaks can be efficiently channeled into alternative pathways in these cells...

..Furthermore, these findings provide a novel link between E2Fs and the transcriptional response to hypoxia and provide insight into the mechanisms by which the tumor microenvironment can contribute to genetic instability in cancer...

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..Together, these findings indicate that ATM plays a role in both crossover control and chromosome axis integrity and further suggests that ATM is important for coordinating these features of meiotic chromosome dynamics...

..However, none of these was found to affect the HDR activity of BARD1, suggesting that any increased cancer risk conferred by these mutations is not because of defects in this repair mechanism...

..As increasing amounts of single-nucleotide polymorphism data emerge, this approach will be useful for investigating the recombination landscape of the mouse genome...

..We propose that RAD51C ensures a tight regulation of RAD51 assembly during DSB repair and plays a direct role in repairing DSBs in vivo...

..These results support a contact-first model in which chromosome translocations predominantly form among spatially proximal DSBs...

..Although SSA can efficiently mediate translocations between identical repeats, its contribution to translocation formation is likely very limited because of sequence divergence between repetitive elements in the genome...

..Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function...

..These results emphasize the fluidity of mammalian DSB repair pathway usage. The intron-based system is highly adaptable to addressing a number of issues regarding molecular mechanisms of genomic rearrangements in mammalian cells...

..The absence of ATM caused defects in folliculogenesis that were similar to those in Dmc1 mutants and that could be suppressed by Spo11 mutation, implying that oocyte death in Atm-deficient animals is a response to defective DSB repair...

..The tumor suppressor activity of BRCA1 may require the participation of BARD1 to maintain chromosome integrity through the homologous-repair pathway...

..Thus, mice deficient in NHEJ provide excellent models to study the etiology of unbalanced translocations and amplification events during tumorigenesis...

..Most importantly, Eme1 deficiency led to spontaneous genomic instability. These results reveal that mammalian Eme1 plays a key role in DNA repair and the maintenance of genome integrity...

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..These results suggest that the increased cancer risk associated with this variant may not be due to an intrinsic HDR defect...

..Increased Rad51 also promoted aneuploidy and multiple chromosomal rearrangements. These data provide a link between elevated Rad51 protein levels, genome instability, and tumor progression...

..The recombination-related breaks in the hot spot likely reflect SPO11-induced double-strand breaks and/or recombination intermediates containing free 3' hydroxyl groups...

..These data indicate that PARP-1 is dispensable in HR induced by DSBs, but is involved in the repair and reactivation of stalled replication forks...

..The substantially increased DNA damage response in the double mutants implies a cooperation of the two DSB repair pathways for survival and genomic integrity in the animal...

..Thus, ATP hydrolysis by RAD51 has a key role in various types of DNA repair in mammalian cells...

..These studies demonstrate a critical role for the proper biallelic expression of the mammalian Mus81 in the maintenance of genomic integrity and tumor suppression...

..These results imply that the proper genetic interplay of repair factors is essential to limit the mutagenic potential of DSB repair...

..These results indicate that extensive LOH is normally suppressed during DSB-induced allelic recombination in dividing mammalian cells...

..Consistent with its ability to target the MRN complex, mirin abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells...

..e., single-strand annealing. These results suggest an early role for the FANC proteins in homologous DSB repair pathway choice...

..Furthermore, Spo11(-/-) mice showed normal serum levels of all Ig isotypes. These results indicate that Spo11 is not required for Ig hypermutation or class switch recombination...

..In addition, these data suggest that Artemis might be the nuclease responsible for nucleotide loss from signal ends during the repair process...

..Together, our results identify RECQL5 as an important tumor suppressor that may act by preventing inappropriate HR events via Rad51 presynaptic filament disruption...

..This is the first study to highlight a function for BCL-x(L) in modulating DSB repair in human cells...

..These reporters can be used to assess the effects of genetic background, dominant-negative constructs, or physiological conditions on DSB repair in a wide variety of mammalian cells...

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..Surprisingly, translocations are increased in cells deficient for the nonhomologous end-joining (NHEJ) protein Ku70, implicating non-canonical joining pathways in their etiology...

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..The roles of a gene encoding a Rad51 paralog (Xrcc2) and other Rad52 epistasis group members (Rad52 and Rad54) will be investigated, as well as that of a hypomorphic Brca2 allele. ..

..This project will address fundamental questions about how mammals control meiotic recombination and respond when there are problems. ..

..This project will address fundamental questions about how mammals control meiotic recombination and respond when there are problems. ..

..We will further explore this relationship by examining spindle formation in cultured Spo11-/- oocytes. We will also explicitly test whether Spo11 is required for meiotic crossing over by assaying chiasma formation in mutant oocytes. ..

..The understanding that is gained has a long-range impact on health, medicine, and basic science. ..

..The roles of a gene encoding a Rad51 paralog (Xrcc2) and other Rad52 epistasis group members (Rad52 and Rad54) will be investigated, as well as that of a hypomorphic Brca2 allele. ..