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

Fatmata Sesay1,2, Hui Zhang1, Priya Kapoor-Vazirani1

  • 1Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.

The Journal of Clinical Investigation
|January 8, 2026
PubMed

Insights

The sirtuin deacetylase SIRT2 deacetylates MRE11 at lysine 393, promoting its DNA binding and facilitating DNA repair. This SIRT2-MRE11 interaction is crucial for the DNA damage response and preventing genomic instability.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • MRE11 is a breast tumor suppressor and key component of the MRN complex, vital for DNA repair pathways.
  • The precise mechanisms regulating MRE11's function in the DNA damage response (DDR) are not fully understood.
  • SIRT2, a sirtuin deacetylase, is also implicated as a breast tumor suppressor.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of MRE11 function in the DNA damage response.
  • To investigate the role of SIRT2 in modulating MRE11 activity.
  • To understand how SIRT2 dysregulation contributes to genomic instability and tumorigenesis.

Main Methods:

  • Investigated the interaction between MRE11 and SIRT2 in response to DNA double-strand breaks (DSBs).
  • Utilized biochemical assays to assess MRE11 deacetylation at lysine 393 (K393) by SIRT2.
  • Examined the impact of MRE11 deacetylation on its DNA binding, localization, and interaction with other proteins.

Main Results:

  • SIRT2 deacetylates MRE11 at K393 in response to DSBs, promoting MRE11's DNA binding and localization to DSBs.
  • SIRT2-mediated deacetylation enhances MRE11's role in DNA end resection and ATM-dependent signaling.
  • This deacetylation does not affect MRE11's interaction with RAD50, NBS1, or CtIP.

Conclusions:

  • SIRT2-mediated deacetylation of MRE11 is a critical upstream mechanism regulating MRE11's DNA binding and function in the DDR.
  • This finding provides insight into how SIRT2's role as a tumor suppressor is linked to maintaining genomic stability.
  • Dysregulation of SIRT2 can lead to impaired DNA repair, genomic instability, and potentially tumorigenesis.
Keywords:
Cell biologyDNA repairOncologyRadiation therapy

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