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

Abstract

AbstractDNA breaks, in particular double-strand breaks (DSBs), produced by radiation and radiomimetic agents are amongst the most toxic forms of DNA damage, in part because they are associated with extensive oxidative chemical modification at the break termini. Prior to the completion of DSB repair, the chemically modified termini associated with radiation-induced damage must be removed. A number of DNA processing enzymes have been implicated in the processing of these ‘dirty ends’, but our knowledge of this process remains limited. Here, we demonstrate a role for the 5’-3’ exonuclease SNM1A in this process. Cells disrupted for SNM1A are sensitive to radiation and radiomimetic agents and show defects in the resolution of the lethal DSB damage they induce. SNM1A is recruited and retained to the sites of complex DNA damage via the concerted action of three highly conserved interaction domains the PBZ, UBZ and PIP box, mediating interactions with poly-ADP-ribose chains, PCNA and the ubiquitinated form of PCNA, respectively. Consistent with its unprecedented capacity to digest DNA containing a wide range of chemically modified nucleotides, we found that SNM1A can resect DNA containing oxidative lesions representative of those induced by radiation damage at break termini. Taken together, our work reveals a crucial role for SNM1A in the repair of toxic DNA breaks.