Role of mammalian Mre11 in classical and alternative nonhomologous end joining

Abstract

The mammalian Mre11-Rad50-Nbs1 (MRN) complex coordinates double strand break (DSB) signaling with repair by homologous recombination and is associated with the H2A.X chromatin response to DSBs, but its role in non-homologous end joining (NHEJ) is less clear. Here we show that Mre11 promotes efficient NHEJ in both wild-type and Xrcc4−/− mouse embryonic stem cells. Depletion of Mre11 reduces use of microhomology during NHEJ in Xrcc4+/+ cells and suppresses end resection in Xrcc4−/− cells, revealing specific roles for Mre11 in both classical and alternative NHEJ. The NHEJ function of Mre11 is independent of H2A.X. We propose a model in which both enzymatic and scaffolding functions of Mre11 cooperate to support mammalian NHEJ.