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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI186711

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

Fatmata Sesay,1 Hui Zhang,1 Priya Kapoor-Vazirani,1 Andrew T. Jung,1 Mark E. Essien,1 Amanda J. Bastien,1 Nho C. Luong,1 Xu Liu,2 PamelaSara E. Head,1 Duc M. Duong,2 Xiaofeng Yang,1 Zachary S. Buchwald,1 Xingming Deng,1 Nicholas T. Seyfried,2 and David S. Yu1

1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

Find articles by Duong, D. in: PubMed | Google Scholar

1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

Find articles by Yang, X. in: PubMed | Google Scholar

1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

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1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

Find articles by Deng, X. in: PubMed | Google Scholar

1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

Find articles by Seyfried, N. in: PubMed | Google Scholar

1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

2Department of Biochemistry, Emory University School of Medicine, Atlanta, United States of America

Find articles by Yu, D. in: PubMed | Google Scholar

Published January 8, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI186711.
Copyright © 2026, Sesay et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 8, 2026 - Version history
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Abstract

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.

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