Abstract

Abstract MRE11 is known to play a role in DNA damage repair through the MRE11-RAD50-NBS1 (MRN) complex and homologous recombination. However, the upstream signaling mechanisms regulating MRE11 in DNA repair are unclear. Here, we aimed to determine the extent to which MRE11 is regulated by deacetylation by the SIRT2 sirtuin deacetylase and tumor suppressor protein. We overexpressed MRE11 in HEK293T cells, induced DNA damage through radiation treatment, and performed a series of co-immunoprecipitation (co-IP) studies with and without ionizing radiation (IR). Additionally, we evaluated the acetylation of MRE11 with and without the presence of SIRT2. In a series of functional experiments, immunofluorescence staining assays were performed in U2OS-265 Fok1 cells with SIRT2 knockdown to determine the effect of on MRE11 recruitment to DNA damage sites. Co-IP studies and in vitro DNA pulldown assays were performed to determine the role of SIRT2 in impacting MRE11 interaction with RAD50 and NBS1 and binding to DNA damage. We also examined for IR-induced RPA70 foci formation and downstream ATM-dependent signaling. We found that SIRT2 interacts with and deacetylates MRE11. Furthermore, SIRT2 deacetylation facilitated MRE11 binding to DNA but not interaction with RAD50 and NBS1. Finally, SIRT2 deacetylation facilitated DNA end resection and ATM-dependent phosphorylation of KAP1. In conclusion, our results define a role for SIRT2 in directing MRE11 localization and binding to DNA to promote DNA end resection and ATM-dependent signaling through deacetylation. Citation Format: Mark Essien, Fatmata Sesay, Hui Zhang, Andrew Jung, David Yu. MRE11 function in DNA damage response is regulated by SIRT2 deacetylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5612.

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