Mitochondrial DNA Fork Protection by Fanconi Anemia Genes Suppresses cGAS Activation

Abstract

Fanconi Anemia patients exhibit bone marrow failure, increased cancer risk, developmental abnormalities, endocrine dysfunction and elevated inflammation. The underlying cause for these pleiotropic disease phenotypes remains enigmatic. Here, we show that Fanconi Anemia genes are required for protecting mitochondrial DNA replication forks upon oxidative damage to suppress mitochondrial genome instability. Specifically, patient cells show a loss of nascent mtDNA caused by MRE11 nuclease degradation. Mitochondrial fork protection requires multiple pathway membersincluding FANCD2, RAD51C, BRCA2, and SLX4, but not Fanconi Anemia core complex genes or FANCD2 mono-ubiquitination, revealing a mechanistic separation between mitochondrial and nuclear FANC genome stability pathways. Importantly, stalled mitochondrial replication fork degradation by MRE11 results in activation of cGAS, thus identifying a nuclease responsible for mitochondrial DNA-dependent induction of the cGAS-inflammation pathway. The collective results establish a molecular pathway for mitochondrial DNA replication stability and explain how defects in genome maintenance proteins cause diverse cellular disease phenotypes.