MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis

Nature. 2024 Jan;625(7995):585-592. doi: 10.1038/s41586-023-06889-6. Epub 2024 Jan 10.


Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression1-3. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)4-10. Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.

MeSH terms

  • Cell Proliferation
  • Cell Transformation, Neoplastic* / metabolism
  • Cell Transformation, Neoplastic* / pathology
  • DNA Damage
  • Genomic Instability
  • Humans
  • MRE11 Homologue Protein* / metabolism
  • Necroptosis
  • Nucleosomes* / metabolism
  • Nucleotidyltransferases* / metabolism
  • Radiation, Ionizing
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology


  • cGAS protein, human
  • MLKL protein, human
  • MRE11 Homologue Protein
  • MRE11 protein, human
  • NBN protein, human
  • Nucleosomes
  • Nucleotidyltransferases
  • RAD50 protein, human
  • RIPK3 protein, human
  • ZBP1 protein, human