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Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
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Stalled replication fork protection limits cGAS-STING and P-body-dependent innate immune signalling

Ahmed Emam1,2, Xiao Wu1, Shengfeng Xu1

  • 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nature Cell Biology
|July 11, 2022
PubMed

Insights

Abnormal replication fork degradation triggers cytosolic DNA accumulation and innate immune responses. Abro1 and FANCD2 proteins prevent this, maintaining genome stability and restricting immune activation.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Immunology

Background:

  • Replication stress and genome instability are linked to immune system activation.
  • Protecting stalled replication forks is vital for cellular response to stress and genome stability.

Purpose of the Study:

  • To investigate the role of Abro1 and FANCD2 in protecting replication forks.
  • To elucidate the connection between replication fork protection and innate immune responses.
  • To explore the therapeutic potential of targeting the replication stress-innate immunity axis.

Main Methods:

  • Assessed the function of Abro1 and FANCD2 in protecting stalled replication forks.
  • Investigated the impact of Abro1 or FANCD2 deficiency on cytosolic DNA accumulation and immune response activation.
  • Utilized DNA2 nuclease assays and cGAS-STING pathway analysis.
  • Examined the role of ribosomal DNA in cGAS binding and P-body formation dynamics.

Main Results:

  • Abro1 and FANCD2 deficiency leads to stalled replication fork degradation, causing cytosolic single-stranded DNA accumulation.
  • This accumulation activates a DNA2 nuclease-dependent, cGAS-STING-mediated innate immune response.
  • Cytosolic DNA includes ribosomal DNA that binds to cGAS, and Abro1/FANCD2 limit replication stress-induced P-body formation.

Conclusions:

  • Abro1 and FANCD2 are critical for protecting replication forks and restricting innate immune activation.
  • The study reveals a mechanism where replication fork degradation triggers immune responses via cytosolic DNA.
  • This link between replication stress and innate immunity offers potential therapeutic targets.

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