MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis

Abstract 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…