MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis

• 成果类型: Article
• 署名作者: 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.
• 署名单位: University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4874
• DOI: 10.1038/s41586-023-06889-6
• 发表日期: 2024-01-18
• 关键词: structural basis; kinase-activity; dna; reveals; cancer

摘要

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. The double-strand break sensor MRE11 is identified as a pivotal mediator of cGAS activation in response to multiple types of DNA damage.