Mre11 liberates cGAS from nucleosome sequestration during tumorigenesis

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS/STING-mediated innate immune signaling and tumor suppression1-3. However, the mechanism for cGAS activation by endogenous DNA damage remains enigmatic, particularly given the constitutive inhibition of cGAS by high-affinity histone acidic patch (AP) binding4-10. Here we report an in vivo CRISPR screen that identified the DNA double strand break sensor Mre11 as a suppressor of mammary tumorigenesis induced by Myc overexpression and p53 deficiency. Mre11 antagonizes Myc-induced proliferation through cGAS/STING activation. Direct binding of the Mre11-Rad50-Nbn (MRN) complex to nucleosomes displaces cGAS from AP sequestration, which is required for DNA damage-induced cGAS mobilization and activation by cytosolic DNA. Mre11 is thereby essential for cGAS activation in response to oncogenic stress, cytosolic DNA transfection, and ionizing radiation. Furthermore, we show Mre11-dependent cGAS activation suppresses Myc-induced proliferation through ZBP1/RIPK3/MLKL-mediated necroptosis. In human triple-negative breast cancer, ZBP1 downregulation correlates with increased genome instability, decreased immune infiltration, and poor patient prognosis. These findings establish Mre11 as a critical link between DNA damage and cGAS activation that regulates tumorigenesis through ZBP1-dependent necroptosis. One-sentence summary Mre11 is required for cGAS activation during oncogenic stress and promotes ZBP1-dependent necroptosis.