Date: 14 Aug 2013
DNA double-strand breaks (DSBs) can be caused by exogenous and endogenous mechanisms, such as ionizing radiation, reactive oxygen species, or replication fork collapse. Efficient repair of DSBs is thus crucial for cells to maintain genome integrity. Mammalian cells have evolved at least two distinct pathways for repairing DSBs, homologous recombination (HR) and nonhomologous end-joining (NHEJ). However, their respective roles in human somatic cells remain to be elucidated.
Prof. Noritaka Adachi, Department of Molecular Biology at Yokohama City University and his colleagues showed using a series of human gene-knockout cell lines that NHEJ repairs nearly all of the topoisomerase II- and low-dose radiation-induced DNA damage, while it negatively affects survival of cells harbouring replication-associated DSBs. Intriguingly, they found that loss of DNA ligase IV, a critical NHEJ ligase, and Artemis, an NHEJ factor with endonuclease activity, independently contribute to increased resistance to replication-associated DSBs. They also showed that loss of Artemis alleviates hypersensitivity of DNA ligase IV-null cells to low-dose radiation- and topoisomerase II-induced DSBs.
Finally, Dr Adachi’s group demonstrated that Artemis-null human cells display increased gene-targeting efficiencies, particularly in the absence of DNA ligase IV. Collectively, these data suggest that DNA ligase IV and Artemis act cooperatively to promote NHEJ, thereby suppressing HR, and that HR may only operate on accidental DSBs when NHEJ is missing or abortive.
This study was published through the journal “PLOS ONE” (14 Aug 2013).