MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis

• Published in: Nature (London) 2024-01, Vol.625 (7995), p.585-592
• Main Authors: Cho, Min-Guk, Kumar, Rashmi J., Lin, Chien-Chu, Boyer, Joshua A., Shahir, Jamshaid A., Fagan-Solis, Katerina, Simpson, Dennis A., Fan, Cheng, Foster, Christine E., Goddard, Anna M., Lerner, Lynn M., Ellington, Simon W., Wang, Qinhong, Wang, Ying, Ho, Alice Y., Liu, Pengda, Perou, Charles M., Zhang, Qi, McGinty, Robert K., Purvis, Jeremy E., Gupta, Gaorav P.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/51; 38; 38/22; 38/47; 38/91; 631/45/147; 631/67/1347; 82; 82/80; 82/83; Binding; Breast cancer; Cell cycle; Cell Proliferation; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; CRISPR; Damage; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; Fibroblasts; Genomes; Genomic Instability; Histones; Humanities and Social Sciences; Humans; Ionizing radiation; Microscopy; MRE11 Homologue Protein - metabolism; MRE11 protein; multidisciplinary; Necroptosis; Nucleosomes - metabolism; Nucleotidyltransferases - metabolism; Radiation, Ionizing; Science; Science (multidisciplinary); Senescence; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumorigenesis; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06889-6

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS–STING-mediated signalling and tumour suppression 1 – 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. The double-strand break sensor MRE11 is identified as a pivotal mediator of cGAS activation in response to multiple types of DNA damage.