生物学导论翻译

Molecular

mechanisms

of DNA double-

strand break repair

Roland Kanaar, Jan H. J. Hoeijmakers

and Dik C. van Gen

DNA double-strand breaks (DSBs) are major threats to the genomic integrity of cells. If not taken care of properly, they can cause chromosome fragmentation, loss and translocation, possibly resulting in carcinogenesis. Upon DSB formation, cell-cycle checkpoints are triggered and multiple DSB repair pathways can be activated. Recent research on the Nijmegen breakage syndrome, which predisposes patients to cancer, suggests a direct link between activation of cell-cycle checkpoints and DSB repair. Furthermore, the biochemical activities of proteins involved in the two major DSB repair pathways, homologous recombination and DNA end-joining, are now beginning to emerge. This review discusses these new findings and their implications for the mechanisms of DSB repair. The integrity of DNA inside cells is constantly being challenged by endogenous and exogenous DNA- damaging agents. Because a large variety of lesions can occur in DNA, it is not surprising that multiple pathways have evolved that each repair a subset of these lesions

1

. The significance of DNA repair is illustrated by the phenotypes of xeroderma pigmen tosum, Cockayne’s syndrome, trich othiodystrophy and hereditary nonpolyposis colorectal cancer pa2,3 . These disorders are caused by mutations in DNA repair genes that predispose the patients to cancer, neurological abnormalities or both. In addi- tion to efficient DNA repair, correct activation of cell-cycle checkpoints upon induction of DNA damage is of crucial importance for the maintenance of genomic integrity. Checkpoints allow actively dividing cells to pause and repair DNA damage before segregation of the replicated genome into daughter cells. Their importance is underscored by inherited disorders associated with defects in activating cellcycle checkpoints such as ataxia telangiectasia and Nijmegen breakage syndrome 4,5. These disorders cause hypersensitivity to DNA-damaging agents and spontaneous chromosomal instability. In this review, we focus on mechanisms of DNA double-strand break (DSB) repair. DSBs are generated by endogenously produced radicals and exogenous agents such as ionizing radiation (IR), whichis often used in anti-cancer therapy. Repair of DSBs

is of cardinal importance to prevent chromosomal fragmentation, translocations and deletions. In the soma, the genomic instability resulting from persistent or incorrectly repaired DSBs can lead to carcinogenesis through activation of oncogenes, inactivation of tumour-suppressor genes or loss of heterozygosity, while in the germline they can lead to inborn defects.

The deleterious effects of DSBs have triggered the evolution of multiple pathways for their repair 6,7. Homologous recombination requires extensive re- gions of DNA homology and repairs DSBs accurately using information on the undamaged sister chromati d or homologous chromosome. DNA end-joining, on the other hand, uses no, or extremely limited, sequence homology to rejoin juxtaposed ends in a manner that need not be error free (Figs 1 and 2; see