MRE11-dependent instability in mitochondrial DNA fork protection activates a cGAS immune signaling pathway

Jessica W. Luzwick, Eszter Dombi, Rebecca A. Boisvert, Sunetra Roy, Soyoung Park, Selvi Kunnimalaiyaan, Steffi Goffart, Detlev Schindler, Katharina Schlacher

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Mitochondrial DNA (mtDNA) instability activates cGAS-dependent innate immune signaling by unknown mechanisms. Here, we find that Fanconi anemia suppressor genes are acting in the mitochondria to protect mtDNA replication forks from instability. Specifically, Fanconi anemia patient cells show a loss of nascent mtDNA through MRE11 nuclease degradation. In contrast to DNA replication fork stability, which requires pathway activation by FANCD2-FANCI monoubiquitination and upstream FANC core complex genes, mitochondrial replication fork protection does not, revealing a mechanistic and genetic separation between mitochondrial and nuclear genome stability pathways. The degraded mtDNA causes hyperactivation of cGAS-dependent immune signaling resembling the unphosphorylated ISG3 response. Chemical inhibition of MRE11 suppresses this innate immune signaling, identifying MRE11 as a nuclease responsible for activating the mtDNA-dependent cGAS/STING response. Collective results establish a previously unknown molecular pathway for mtDNA replication stability and reveal a molecular handle to control mtDNA-dependent cGAS activation by inhibiting MRE11 nuclease.

Original languageEnglish (US)
Article numbereabf9441
JournalScience Advances
Volume7
Issue number51
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • General

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