Abstract
Repair of DNA double strand breaks (DSBs) by homologous recombination (HR) is critical for survival and genome stability of individual cells and organisms, but also contributes to the genetic diversity of species. A critical step in HR is MRN/CtIP-dependent end-resection that generates the 3′ single-stranded DNA overhangs required for the subsequent strand exchange reaction. Here, we identify EXD2 (EXDL2) as an exonuclease essential for DSB resection and efficient HR. EXD2 is recruited to chromatin in a damage-dependent manner and confers resistance to DSB-inducing agents. EXD2 functionally interacts with the MRN-complex to accelerate resection via its 3′-5′ exonuclease activity that efficiently processes dsDNA substrates containing nicks. Finally, we establish that EXD2 stimulates both short and long-range DSB resection, and thus together with MRE11 is required for efficient HR. This establishes a key role for EXD2 in controlling the initial steps of chromosomal break repair.
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