MRE11 deacetylation by SIRT2 promotes DNA binding to facilitate DNA end resection and ATM-dependent signaling

MRE11, a breast tumor suppressor and component of the MRE11-RAD50-NBS1 (MRN) complex, plays a critical role in DNA end resection and initiation of ATM-dependent DNA damage signaling.However, the precise mechanisms governing MRE11 function in the DNA damage response (DDR) remain incompletely understood.Here, we found that MRE11 is deacetylated by the SIRT2 sirtuin deacetylase and breast tumor suppressor, which promotes DNA binding to facilitate DNA end resection and ATM-dependent signaling.SIRT2 deacetylase activity promoted DNA end resection.SIRT2 further complexed with and deacetylated MRE11 at conserved lysine (K) 393 in response to DNA double-strand breaks (DSBs), which promoted MRE11 localization and DNA binding at DSBs but not interaction with RAD50, NBS1, or CtIP.Moreover, MRE11 K393 deacetylation by SIRT2 promoted ATM-dependent signaling.Our findings define a mechanism regulating MRE11 binding to DNA through SIRT2 deacetylation, elucidating a critical upstream signaling event directing MRE11 function in the DDR and providing insight into how SIRT2 dysregulation leads to genomic instability and tumorigenesis.MRE11 binds to single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) directly through both amino-terminal and carboxyl-terminal DNA binding domains (9,12,(46)(47)(48)(49)(50).This interaction is also facilitated by as well as indirectly mediated by RAD50 (49, 51, 52) and NBS1 (48, 53, 54), which are critical for MRE11 activities in the DDR.However, the mechanisms regulating MRE11 recruitment and binding to DNA are not well understood.MRE11 has been reported to be modified by lactylation (55) and methylation (56-59), which promote DNA binding, and phosphorylation which dissociates it from chromatin (60-63).However, a role for acetylation in directing MRE11's functions in the DDR remains unclear.Sirtuin 2 (SIRT2), an NAD+-dependent deacetylase, is recognized for its role in diverse biological processes, including genome maintenance, tumor suppression, aging, and metabolism (64-67).Studies involving mice lacking Sirt2 have demonstrated an increased susceptibility to breast, liver, and other cancer types, suggesting a role for SIRT2 in tumor suppression (68, 69).Moreover, somatic cancer-associated SIRT2 mutations impair SIRT2's activity in genome maintenance (70), suggesting a role for SIRT2 in tumor suppression that may be attributed, at least in part, to a role in genome maintenance.Indeed, SIRT2 acts as a central regulator of DDR pathways by modulating the acetylation status of several proteins involved in the DDR, including ATRIP (71), BARD1 (72), RAD52 (73), CDK9 (74), and DNA-PKcs (75).However, a role for SIRT2, and more generally of sirtuins, in regulating MRE11 function as well as a role for SIRT2 in directing DNA end resection and ATM checkpoint signaling, which are facilitated by MRE11, is not known.Here, we show that MRE11 deacetylation at conserved K393 by SIRT2 promotes its localization and binding to DNA at DSBs to promote DNA end resection and ATM-dependent signaling.Our findings define a mechanism governing MRE11 function in the DDR, elucidating