Stalled Replication Fork Protection Limits cGAS-STING and P-Body-Dependent Innate Immune Signalling

Authors

Ahmed Emam
Xiao Wu
Shengfeng Xu
Longqiang Wang
Shichang Liu
Bin Wang

Publication Date

7-1-2022

Journal

Nature Cell Biology

Abstract

Protection of stalled replication forks is crucial for cells to respond to replication stress and maintain genome stability. Genome instability and replication stress have been linked to immune activation. Here we show that Abro1 and FANCD2 protect replication forks, which is linked with the restriction of innate immune responses. We reveal that stalled replication fork degradation induced by Abro1 or FANCD2 deficiency leads to accumulation of cytosolic single-stranded DNA and activation of a cGAS-STING-dependent innate immune response that is dependent on DNA2 nuclease. We further show that the increased cytosolic single-stranded DNA contains ribosomal DNA that can bind to cGAS. In addition, Abro1 and FANCD2 limit the formation of replication stress-induced P-bodies, and P-bodies are capable of modulating activation of the innate immune response after prolonged replication stress. Our study demonstrates a connection between replication stress and activation of the innate immune response that may be targeted for therapeutic purpose.

Keywords

DNA Replication, DNA, Single-Stranded, Genomic Instability, Humans, Immunity, Innate, Nucleotidyltransferases, Processing Bodies

DOI

10.1038/s41556-022-00950-8

PMID

35817959

PMCID

PMC9924303

PubMedCentral® Posted Date

7-11-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes