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

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Τίτλος: MRE11 deacetylation by SIRT2 promotes DNA binding to facilitate DNA end resection and ATM-dependent signaling.
Συγγραφείς: Sesay F; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.; Department of Biology, Clark Atlanta University, Atlanta, Georgia, USA., Zhang H; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Kapoor-Vazirani P; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Jung AT; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Essien ME; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Bastien AJ; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Luong NC; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Liu X; Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA., Head PE; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Duong DM; Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA., Yang X; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Buchwald ZS; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Deng X; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA., Seyfried NT; Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA., Yu DS; Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Πηγή: The Journal of clinical investigation [J Clin Invest] 2026 Jan 08; Vol. 136 (5). Date of Electronic Publication: 2026 Jan 08 (Print Publication: 2026).
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: eCollection Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
Imprint Name(s): Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
Ιατρικοί όροι (MeSH): MRE11 Homologue Protein*/metabolism , MRE11 Homologue Protein*/genetics , Ataxia Telangiectasia Mutated Proteins*/metabolism , Ataxia Telangiectasia Mutated Proteins*/genetics , Sirtuin 2*/metabolism , Sirtuin 2*/genetics , DNA-Binding Proteins*/metabolism , DNA-Binding Proteins*/genetics , DNA*/metabolism , DNA*/genetics , Signal Transduction* , DNA Breaks, Double-Stranded*, Humans ; Acetylation ; Animals ; DNA Repair ; Protein Binding
Περίληψη: MRE11, a breast tumor suppressor and component of the MRE11-RAD50-NBS1 complex, plays a critical role in DNA end resection and initiation of ataxia-telangiectasia mutation-dependent (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 393 (K393) in response to DNA double-stranded 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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Grant Information: K99 GM157498 United States GM NIGMS NIH HHS; R01 CA301614 United States CA NCI NIH HHS; R01 AI136581 United States AI NIAID NIH HHS; U54 CA274513 United States CA NCI NIH HHS; P30 CA138292 United States CA NCI NIH HHS; R01 AI162633 United States AI NIAID NIH HHS; F31 CA225124 United States CA NCI NIH HHS; R01 CA178999 United States CA NCI NIH HHS; R01 CA254403 United States CA NCI NIH HHS; R35 GM155032 United States GM NIGMS NIH HHS
Contributed Indexing: Keywords: Cell biology; DNA repair; Oncology; Radiation therapy
Substance Nomenclature: EC 3.1.- (MRE11 Homologue Protein)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
EC 3.5.1.- (Sirtuin 2)
0 (MRE11 protein, human)
0 (DNA-Binding Proteins)
EC 3.5.1.- (SIRT2 protein, human)
EC 2.7.11.1 (ATM protein, human)
9007-49-2 (DNA)
Entry Date(s): Date Created: 20260108 Date Completed: 20260609 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC12948433
DOI: 10.1172/JCI186711
PMID: 41505211
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1558-8238
DOI:10.1172/JCI186711