TY - JOUR
T1 - MRE11-dependent instability in mitochondrial DNA fork protection activates a cGAS immune signaling pathway
AU - Luzwick, Jessica W.
AU - Dombi, Eszter
AU - Boisvert, Rebecca A.
AU - Roy, Sunetra
AU - Park, Soyoung
AU - Kunnimalaiyaan, Selvi
AU - Goffart, Steffi
AU - Schindler, Detlev
AU - Schlacher, Katharina
N1 - Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.abf9441
DO - 10.1126/sciadv.abf9441
M3 - Article
C2 - 34910513
AN - SCOPUS:85121864897
SN - 2375-2548
VL - 7
JO - Science Advances
JF - Science Advances
IS - 51
M1 - eabf9441
ER -