SNM1A (DCLRE1A) is crucial for efficient repair of complex DNA breaks in human cells

Abstract

DNA double-strand breaks (DSBs) are one of the most cytotoxic forms of damage, with even small number of unrepaired breaks being potentially lethal1. In human cells, the majority of DSBs are resolved by one of two pathways, that is non-homologous end-joining (active from G1- through to the G2-phase of the cell cycle) or homologous recombination (which is activated as cells traverse S-phase)2. Prior to completion of DSB repair, any chemically modified nucleotides or aberrant structures must be removed from the break-ends. This process is especially important for DSBs induced by ionising radiation (IR) or radiomimetic drugs, including bleomycin and related agents, which are associated with extensive, mostly oxidative, DNA modifications at the break termini3,4. Various factors have been implicated in processing such ‘dirty end’ ends, including tyrosyl DNA phosphodiesterase (TDP1)5, polynucleotide kinase (PNK)6, aprataxin7-10 and Artemis/SNM1C (discussed below)11,12. TDP1 can remove the 3ʹ-phosphoglycolate ends that constitute approximately 10% of the termini produced by IR13. PNK catalyses removal of 3ʹ-phosphate groups and addition of phosphates to 5ʹ-hydroxyl moieties in preparation for end ligation6, modifications that are associated with oxidation reactions following IR. Aprataxin catalyses deadenylation releasing DNA Ligase IV during abortive ligation reactions during NHEJ, removing the associated AMP group14.