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MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis

Min-Guk Cho1, Rashmi J Kumar1,2, Chien-Chu Lin3

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Nature
|January 10, 2024
PubMed

Insights

The MRE11 complex releases cGAS from inhibition, enabling DNA damage-induced activation. This process suppresses breast cancer by triggering necroptosis, highlighting MRE11

Area of Science:

  • Molecular Biology
  • Immunology
  • Cancer Research

Background:

  • Oncogene-induced replication stress causes DNA damage, activating cGAS-STING signaling for tumor suppression.
  • The mechanism of cGAS activation by endogenous DNA damage is unclear, as histone binding inhibits it.
  • MRE11 (meiotic recombination 11) is a DNA double-strand break sensor involved in DNA repair.

Purpose of the Study:

  • To elucidate the role of MRE11 in regulating cGAS activation by endogenous DNA damage.
  • To investigate the mechanism by which MRE11 facilitates cGAS activation.
  • To determine the downstream consequences of MRE11-mediated cGAS activation in tumor suppression.

Main Methods:

  • Investigated the interaction between MRE11-RAD50-NBN complex, nucleosomes, and cGAS.
  • Assessed the necessity of MRE11 for cGAS activation in response to oncogenic stress, dsDNA, and ionizing radiation.
  • Analyzed the role of MRE11-dependent cGAS activation in ZBP1-RIPK3-MLKL-mediated necroptosis and tumor suppression.

Main Results:

  • MRE11 binding to nucleosome fragments displaces cGAS from inhibitory histone interactions, enabling dsDNA-dependent activation.
  • MRE11 is essential for cGAS activation by endogenous DNA damage, cytosolic dsDNA, and ionizing radiation.
  • MRE11-mediated cGAS activation promotes ZBP1-RIPK3-MLKL-dependent necroptosis, suppressing mammary tumorigenesis.

Conclusions:

  • MRE11 acts as a crucial mediator linking DNA damage to cGAS activation.
  • MRE11-dependent cGAS activation suppresses breast cancer through ZBP1-mediated necroptosis.
  • Downregulation of ZBP1 correlates with poor prognosis in triple-negative breast cancer.

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