The yeast Fun30 and human SMARCAD1 chromatin remodellers promote DNA end resection

Fun30 and SMARCAD1 are identified as chromatin remodellers that promote DNA end resection during DNA repair and preserve genome stability in yeast and humans, respectively. Double-stranded DNA primed for repair For breakages in double-stranded DNA to be repaired, the 5′ terminal strand is resected to yield a 3′ terminal single-stranded tail. How resection occurs in the context of chromatin was unknown. The laboratories of Grzegorz Ira and Bertrand Llorente have identified the yeast Fun30 and human SMARCAD1 proteins as the chromatin re-modellers that facilitate resection. Fun30 is also required to overcome the inhibition of resection that occurs owing to binding of Rad9, a checkpoint adaptor protein, to the 5′ end of the break. Several homology-dependent pathways can repair potentially lethal DNA double-strand breaks (DSBs). The first step common to all homologous recombination reactions is the 5′–3′ degradation of DSB ends that yields the 3′ single-stranded DNA required for the loading of checkpoint and recombination proteins. In yeast, the Mre11–Rad50–Xrs2 complex (Xrs2 is known as NBN or NBS1 in humans) and Sae2 (known as RBBP8 or CTIP in humans) initiate end resection, whereas long-range resection depends on the exonuclease Exo1, or the helicase–topoisomerase complex Sgs1–Top3–Rmi1 together with the endonuclease Dna2 (refs 1–6 ). DSBs occur in the context of chromatin, but how the resection machinery navigates through nucleosomal DNA is a process that is not well understood 7 . Here we show that the yeast Saccharomyces cerevisiae Fun30 protein and its human counterpart SMARCAD1 (ref. 8 ), two poorly characterized ATP-dependent chromatin remodellers of the Snf2 ATPase family, are directly involved in the DSB response. Fun30 physically associates with DSB ends and directly promotes both Exo1- and Sgs1-dependent end resection through a mechanism involving its ATPase activity. The function of Fun30 in resection facilitates the repair of camptothecin-induced DNA lesions, although it becomes dispensable when Exo1 is ectopically overexpressed. Interestingly, SMARCAD1 is also recruited to DSBs, and the kinetics of recruitment is similar to that of EXO1. The loss of SMARCAD1 impairs end resection and recombinational DNA repair, and renders cells hypersensitive to DNA damage resulting from camptothecin or poly(ADP-ribose) polymerase inhibitor treatments. These findings unveil an evolutionarily conserved role for the Fun30 and SMARCAD1 chromatin remodellers in con