Double Strand Break Repair Mechanisms in Mammalian Cells

Abstract

Double-strand breaks (DSBs) represent major threats in chromosomal DNA. They arise either as intermediate structures during recombination, replication and repair events or as potentially lethal lesions introduced by ionising radiation or drugs. In any case, DSBs have to be eliminated immediately, because of the recombinogenic capacity of the DNA ends generated by the DSB that increases the risk for undesired chromosomal aberrations (CAs). In order to cope with DSBs, cells exhibit two different sets of repair activities, namely non-homlogous end joining (NHEJ) and homologous recombinational repair (HRR). Both pathways are regulated during the cell cycle with peak activities either in G1 phase (NHEJ) or in late S and G2 phases (HRR). While NHEJ has the capacity to join arbitrary DNA ends together, HRR depends on the presence of a second undamaged sequence in the genome providing a template for the reconstitution of the sequence at the DSB site. While most of the proteins identified so far participate in one of the two repair pathways, a few proteins are known to participate in both pathways. These last group of proteins is supposed to be involved in the selection process of the DNA repair pathway. Mutations in one DSB repair system result in the accumulation of DSBs and increased levels of CAs. As a result, genome instability is observed in cells with impaired DSB repair functions.