MRE11-Dependent Instability in Mitochondrial DNA Fork Protection Activates cGAS Inflammation
Social Science Research Network(2020)
摘要
Mitochondrial DNA instability activates cGAS and the innate immune system by unknown mechanisms. Here, we find that Fanconi anemia suppressor genes are acting in the mitochondria to protect mitochondrial DNA replication forks from instability. Specifically, Fanconi anemia patient cells show a loss of nascent mitochondrial DNA through MRE11 nuclease degradation. In stark contrast to DNA replication stability in the nucleus, which requires pathway activation by FANCD2 mono ubiquitination and upstream FANC core complex genes, mitochondrial replication fork protection does not, uncovering a mechanistic and genetic separation between mitochondrial and nuclear genome stability pathways. The degraded mitochondrial DNA causes a hyperactivation of the cGAS dependent unphosphorylated ISG3 interferon type-1 response. Importantly, chemical inhibition of MRE11 suppresses this type of inflammation, identifying MRE11 as the nuclease responsible for activating the mitochondrial DNA-dependent cGAS/STING inflammation pathway. Overall, collective results establish a previously unknown molecular pathway for mitochondrial DNA replication stability and show how defects in tumor suppressor proteins cause diverse disease phenotypes including inflammation. Specifically, these findings reveal a molecular handle to control mitochondrial DNA-dependent cGAS activation by inhibiting MRE11 nuclease, relevant to future targeted pharmacological control of specific inflammation responses.
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关键词
mitochondrial dna fork protection,mitochondrial dna,inflammation
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