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DNA Double-Strand Break Repair by Homologous Recombination

DNA double-strand breaks (DSB) are genotoxic DNA lesions that pose problems for DNA transcription, replication and segregation. Improper processing of DSB gives rise to chromosomal instability that can result in carcinogenesis through activation of proto-oncogenes or inactivation of tumor suppressor genes. DSB are caused by exogenous sources such as UV radiation, mechanical stress, ionizing radiation, as well as by endogenous sources such as radicals generated during metabolic processes and genotoxic chemicals. Eukaryotes have evolved two distinct pathways of DSB repair- homologous recombination (HR) and non-homologous end joining (NHEJ). The fundamental difference between these pathways is their dependence on DNA homology and accuracy of repair...

DNA Double-Strand Break Repair by Homologous Recombination

Pathway Summary

DNA double-strand breaks (DSB) are genotoxic DNA lesions that pose problems for DNA transcription, replication and segregation. Improper processing of DSB gives rise to chromosomal instability that can result in carcinogenesis through activation of proto-oncogenes or inactivation of tumor suppressor genes. DSB are caused by exogenous sources such as UV radiation, mechanical stress, ionizing radiation, as well as by endogenous sources such as radicals generated during metabolic processes and genotoxic chemicals. Eukaryotes have evolved two distinct pathways of DSB repair- homologous recombination (HR) and non-homologous end joining (NHEJ). The fundamental difference between these pathways is their dependence on DNA homology and accuracy of repair. In general, HR ensures an accurate repair by using the undamaged sister chromatid or homologous chromosome as a template. NHEJ, on the other hand, uses no or extremely limited sequence homology to rejoin ends in a manner that need not be error free.The initial cellular response to DSB is mediated through ATM and the MRN complex (Mre11-Rad50-NBS1). In response to DSB, ATM in effect 'raises the alarm' to DNA damage, phosphorylating many downstream effector targets such as p53, H2AX, Mdm2, BRCA11, c-Abl and Chk2. This swift response acts to halt the cell cycle and stop DNA replication. ATM then facilitates DNA repair or triggers apoptosis based on the severity of the damage. The MRN complex has 3 critical roles in DSB sensing: stabilization, signaling and effector scaffolding. Subsequent steps of DSB repair include DNA end recognition and nucleolytic processing of the broken ends of DNA into 3' end ssDNA. Rad51 along with ssDNA forms the helical nucleoprotein filament that promotes DNA strand exchange. Rad54 interacts with this nucleoprotein filament and stimulates its DNA pairing activity. The binding of RAD54 significantly stabilizes the Rad51 nucleoprotein filament. The Rad54 stabilized nucleoprotein filament is more competent in DNA strand exchange and acts over a broader range of solution conditions. The roles played by BRCA1 and BRCA2 in DSB repair by HR appear to be somewhat different. Despite the apparent dissimilarity in protein sequence and structure, both BRCA1 and BRCA2 have common biological functions. Both are localized to the nucleus in somatic cells, where they co-exist in characteristic subnuclear foci that redistribute following DNA damage. BRCA2 controls the intracellular transport and function of Rad51. In addition, BRCA2 also appears to control the enzymatic activity of Rad51.Once the homologous DNA has been identified, subsequent steps lead to strand invasion and D-loop formation. The damaged DNA strand invades the undamaged DNA duplex in a process referred to as DNA strand exchange. Upon joint molecule formation and DNA synthesis, branched DNA structures called Holliday junctions can form as late intermediates in HR. Holliday junctions can slide or 'branch-migrate' along the joined DNAs. Branch migration extends the heteroduplex DNA region between identical recombination partners, and might thereby provide a mechanism to prevent recombination between repetitive sequences that are dispersed throughout the genome. A DNA polymerase then extends the 3' end of the invading strand, and subsequent ligation by DNA ligase I yields a heteroduplexed DNA structure. Completion of recombination requires the resolution of Holliday junctions in order to separate the recombining partners. One well-characterized way of resolving Holliday junctions requires the enzymatic action of a resolvase. This recombination intermediate is resolved and the precise, error-free correction of the DSB is complete.

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