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Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity

Antao Chang1,2, Liang Liu1,3, Justin M Ashby1

  • 1Department of Cancer Biology, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd, Winston-Salem, North Carolina.

Cancer Research
|April 15, 2021
PubMed

Insights

Mutations in KMT2 genes are common in non-small cell lung cancer (NSCLC). KMT2C plays a key role in DNA damage response, and KMT2C/D mutations predict response to PARP inhibitors in NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) typically activate transcription by methylating H3K4.
  • KMT2 gene mutations are frequently observed in non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To investigate the role of KMT2 mutations in NSCLC.
  • To explore the function of KMT2C in DNA damage response (DDR).
  • To identify KMT2C/D mutations as biomarkers for PARP inhibitor (PARPi) therapy in NSCLC.

Main Methods:

  • Analysis of KMT2 mutation frequency in NSCLC.
  • Investigating KMT2C recruitment to DNA damage sites.
  • Assessing the impact of KMT2C/D mutations on homologous recombination (HR) repair.
  • Evaluating PARPi sensitivity in NSCLC with KMT2C/D mutations.

Main Results:

  • KMT2 mutations are frequent in NSCLC, correlating with high mutation loads and poor survival.
  • KMT2C is recruited to DNA damage sites, mediating H3K4 methylation, chromatin relaxation, and amplifying DDR signals.
  • KMT2C/D mutations impair HR-mediated DNA repair, sensitizing NSCLC to PARPi.
  • KMT2C/D mutations serve as biomarkers for PARPi efficacy in NSCLC, particularly when BRCA1/2 mutations are rare.

Conclusions:

  • KMT2C has a novel, transcription-independent role in DNA damage response.
  • High-frequency KMT2C/D mutations are significant biomarkers for PARPi therapy in NSCLC and other cancers.
  • This finding expands the utility of PARPi beyond BRCA1/2-mutated cancers.

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