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

Jessica W Luzwick1, Eszter Dombi1, Rebecca A Boisvert1

  • 1Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA.

Science Advances
|December 15, 2021
PubMed

Insights

Fanconi anemia genes protect mitochondrial DNA (mtDNA) from MRE11 nuclease degradation, preventing cGAS-STING immune pathway overactivation. Inhibiting MRE11 controls this innate immune signaling.

Area of Science:

  • Mitochondrial biology
  • Innate immunity
  • Genome stability

Background:

  • Mitochondrial DNA (mtDNA) instability triggers cGAS-dependent innate immune signaling through poorly understood mechanisms.
  • Fanconi anemia (FA) pathway genes are implicated in DNA repair and genome stability.

Purpose of the Study:

  • To elucidate the mechanisms by which mtDNA instability activates innate immunity.
  • To identify the role of Fanconi anemia genes in mitochondrial genome stability and innate immune response.

Main Methods:

  • Analysis of Fanconi anemia patient cells.
  • Investigation of mitochondrial DNA replication fork stability.
  • Assessment of cGAS-STING pathway activation.
  • Chemical inhibition of MRE11 nuclease.

Main Results:

  • Fanconi anemia suppressor genes protect mitochondrial mtDNA replication forks from MRE11-mediated degradation.
  • Mitochondrial replication fork protection is independent of canonical FANCD2-FANCI monoubiquitination.
  • Degraded mtDNA hyperactivates cGAS-dependent innate immune signaling.
  • MRE11 inhibition suppresses mtDNA-induced cGAS/STING activation.

Conclusions:

  • Fanconi anemia genes maintain mitochondrial genome stability by preventing MRE11 degradation of mtDNA.
  • A mechanistic and genetic separation exists between nuclear and mitochondrial genome stability pathways.
  • MRE11 is a key nuclease mediating mtDNA-dependent cGAS/STING immune activation, representing a therapeutic target.

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