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Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy

Lianhui Sun1, Guangjian Fan1, Zhuqing Zhang1

  • 1Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, China.

Cell Reports
|February 5, 2025
PubMed

Insights

Cancer cells evade chemotherapy by downregulating DNA mismatch repair (MMR) via SIRT7 protein, which destabilizes MSH2. This promotes microsatellite instability (MSI) and drug resistance, suggesting SIRT7 as a therapeutic target.

Area of Science:

  • Molecular Oncology
  • Genomic Stability
  • Cancer Drug Resistance

Background:

  • Drug resistance limits chemotherapy efficacy.
  • DNA mismatch repair (MMR) maintains genomic stability.
  • Cancer cells develop drug resistance by downregulating MMR, increasing microsatellite instability (MSI).

Purpose of the Study:

  • Investigate mechanisms of MMR protein downregulation during DNA-damaging treatments.
  • Clarify the role of SIRT7 in MMR deficiency and drug resistance.

Main Methods:

  • Analysis of SIRT7 and MSH2 protein levels in cervical and lung cancer tissues.
  • Investigating the molecular interactions between SIRT7, MSH2, and ATM kinase.
  • Assessing the impact of SIRT7 on MMR, MSI, and drug resistance.

Main Results:

  • A negative correlation was observed between SIRT7 and MSH2 protein levels.
  • SIRT7 destabilizes MSH2, leading to MSI and mutagenesis.
  • DNA damage induces ATM-dependent phosphorylation and redistribution of SIRT7, impairing MMR and conferring drug resistance.

Conclusions:

  • SIRT7 drives MMR downregulation under therapeutic stress.
  • ATM-dependent SIRT7 phosphorylation is a potential predictive biomarker for chemotherapeutic efficacy.
  • SIRT7 represents a potential therapeutic target for overcoming cancer drug resistance.
Keywords:
ATMCP: CancerCP: Molecular biologySIRT7adaptive mutabilitymicrosatellite instabilitymismatch repair

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