MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis

Min-Guk Cho, Rashmi J. Kumar, Chien-Chu Lin, Joshua A. Boyer, Jamshaid A. Shahir, Katerina Fagan-Solis, Dennis A. Simpson, Cheng Fan, Christine E. Foster, Anna M. Goddard, Lynn M. Lerner, Simon W. Ellington, Qinhong Wang, Ying Wang, Alice Y. Ho, Pengda Liu, Charles M. Perou, Qi Zhang, Robert K. McGinty, Jeremy E. Purvis and Gaorav P. Gupta ()
Additional contact information
Min-Guk Cho: University of North Carolina at Chapel Hill
Rashmi J. Kumar: University of North Carolina at Chapel Hill
Chien-Chu Lin: University of North Carolina at Chapel Hill
Joshua A. Boyer: University of North Carolina at Chapel Hill
Jamshaid A. Shahir: University of North Carolina at Chapel Hill
Katerina Fagan-Solis: University of North Carolina at Chapel Hill
Dennis A. Simpson: University of North Carolina at Chapel Hill
Cheng Fan: University of North Carolina at Chapel Hill
Christine E. Foster: University of North Carolina at Chapel Hill
Anna M. Goddard: University of North Carolina at Chapel Hill
Lynn M. Lerner: University of North Carolina at Chapel Hill
Simon W. Ellington: University of North Carolina at Chapel Hill
Qinhong Wang: University of North Carolina at Chapel Hill
Ying Wang: University of North Carolina at Chapel Hill
Alice Y. Ho: Massachusetts General Hospital
Pengda Liu: University of North Carolina at Chapel Hill
Charles M. Perou: University of North Carolina at Chapel Hill
Qi Zhang: University of North Carolina at Chapel Hill
Robert K. McGinty: University of North Carolina at Chapel Hill
Jeremy E. Purvis: University of North Carolina at Chapel Hill
Gaorav P. Gupta: University of North Carolina at Chapel Hill

Nature, 2024, vol. 625, issue 7995, 585-592

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-023-06889-6

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