The role of double-strand break repair — insights from human genetics

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Abstract
DNA-damage-response mechanisms encompass pathways of DNA-repair and signal-transduction processes that regulate cell-cycle-checkpoint arrest and/or apoptosis. The signal-transduction processes can regulate at least some aspects of DNA repair. There are two main double-strand break (DSB) repair pathways — homologous recombination and non-homologous end-joining (NHEJ). The main signal-transduction pathway that responds to a DSB is regulated by ataxia telangiectasia mutated (ATM), the protein that is defective in the hereditary disorder ataxia telangiectasia. Ataxia telangiectasia and RAD3-related (ATR) probably also has a supporting role in the response to DSBs. Coupling occurs between ATM-dependent signalling and DSB repair. ATM regulates Artemis-dependent processing of a subset of DNA ends, which is required before rejoining by NHEJ can occur. Several human congenital disorders with defects in damage-response mechanisms to DSBs have been described. These include, LIG4 syndrome, severe combined immunodeficiency with sensitivity to ionizing radiation, ataxia telangiectasia, ataxia telangiectasia-like disorder, Nijmegen breakage syndrome, ATR-Seckel syndrome and Fanconi anaemia, as exemplified by FANCD1 (Fanconi anaemia complementation group D1) deficiency. These disorders are associated with a pleiotropic range of clinical features that demonstrate the important role that the damage-response processes have during development. Clinical features include immunodeficiency, development delay and microcephaly, cancer development and premature ageing. The damage-response mechanisms function to maintain genomic stability in somatic cells. During V(D)J recombination and class-switch recombination, the damage-response proteins function to enhance genomic diversity at defined regions. Therefore, immunodeficiency is observed in some of the human DSB-repair-defective disorders. Assays for diagnosis of damage-response disorders are now available and strategies for palliative treatment are beginning to emerge.