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      The Mechanism of Double-Strand DNA Break Repair by the Nonhomologous DNA End-Joining Pathway

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      Annual Review of Biochemistry

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          Abstract

          Double-strand DNA breaks are common events in eukaryotic cells, and there are two major pathways for repairing them: homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). The various causes of double-strand breaks (DSBs) result in a diverse chemistry of DNA ends that must be repaired. Across NHEJ evolution, the enzymes of the NHEJ pathway exhibit a remarkable degree of structural tolerance in the range of DNA end substrate configurations upon which they can act. In vertebrate cells, the nuclease, DNA polymerases, and ligase of NHEJ are the most mechanistically flexible and multifunctional enzymes in each of their classes. Unlike repair pathways for more defined lesions, NHEJ repair enzymes act iteratively, act in any order, and can function independently of one another at each of the two DNA ends being joined. NHEJ is critical not only for the repair of pathologic DSBs as in chromosomal translocations, but also for the repair of physiologic DSBs created during variable (diversity) joining [V(D)J] recombination and class switch recombination (CSR). Therefore, patients lacking normal NHEJ are not only sensitive to ionizing radiation (IR), but also severely immunodeficient.

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          Mechanism of eukaryotic homologous recombination.

          Homologous recombination (HR) serves to eliminate deleterious lesions, such as double-stranded breaks and interstrand crosslinks, from chromosomes. HR is also critical for the preservation of replication forks, for telomere maintenance, and chromosome segregation in meiosis I. As such, HR is indispensable for the maintenance of genome integrity and the avoidance of cancers in humans. The HR reaction is mediated by a conserved class of enzymes termed recombinases. Two recombinases, Rad51 and Dmc1, catalyze the pairing and shuffling of homologous DNA sequences in eukaryotic cells via a filamentous intermediate on ssDNA called the presynaptic filament. The assembly of the presynaptic filament is a rate-limiting process that is enhanced by recombination mediators, such as the breast tumor suppressor BRCA2. HR accessory factors that facilitate other stages of the Rad51- and Dmc1-catalyzed homologous DNA pairing and strand exchange reaction have also been identified. Recent progress on elucidating the mechanisms of action of Rad51 and Dmc1 and their cohorts of ancillary factors is reviewed here.
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            Hydroperoxide metabolism in mammalian organs.

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              Meiotic chromosomes: integrating structure and function.

              Meiotic chromosomes have been studied for many years, in part because of the fundamental life processes they represent, but also because meiosis involves the formation of homolog pairs, a feature which greatly facilitates the study of chromosome behavior. The complex events involved in homolog juxtaposition necessitate prolongation of prophase, thus permitting resolution of events that are temporally compressed in the mitotic cycle. Furthermore, once homologs are paired, the chromosomes are connected by a specific structure: the synaptonemal complex. Finally, interaction of homologs includes recombination at the DNA level, which is intimately linked to structural features of the chromosomes. In consequence, recombination-related events report on diverse aspects of chromosome morphogenesis, notably relationships between sisters, development of axial structure, and variations in chromatin status. The current article reviews recent information on these topics in an historical context. This juxtaposition has suggested new relationships between structure and function. Additional issues were addressed in a previous chapter (551).
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                Author and article information

                Journal
                Annual Review of Biochemistry
                Annu. Rev. Biochem.
                Annual Reviews
                0066-4154
                1545-4509
                June 07 2010
                June 07 2010
                : 79
                : 1
                : 181-211
                Affiliations
                [1 ]Norris Comprehensive Cancer Center, Departments of Pathology, Biochemistry and Molecular Biology, Molecular Microbiology and Immunology, and Biological Sciences, University of Southern California Keck School of Medicine, Los Angeles, California 90089; email:
                Article
                10.1146/annurev.biochem.052308.093131
                3079308
                20192759
                © 2010

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