Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

Abstract

DNA repair via homologous recombination (HR) is indispensable for genome integrity and cell survival but if unrestrained can result in undesired chromosomal rearrangements. The regulatory mechanisms of HR are not fully understood. Cyclic GMP‐AMP synthase (cGAS) is best known as a cytosolic innate immune sensor critical for the outcome of infections, inflammatory diseases, and cancer. Here, we report that cGAS is primarily a chromatin‐bound protein that inhibits DNA repair by HR, thereby accelerating genome destabilization, micronucleus generation, and cell death under conditions of genomic stress. This function is independent of the canonical STING‐dependent innate immune activation and is physiologically relevant for irradiation‐induced depletion of bone marrow cells in mice. Mechanistically, we demonstrate that inhibition of HR repair by cGAS is linked to its ability to self‐oligomerize, causing compaction of bound template dsDNA into a higher‐ordered state less amenable to strand invasion by RAD51‐coated ssDNA filaments. This previously unknown role of cGAS has implications for understanding its involvement in genome instability‐associated disorders including cancer.

Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis

“…Micronuclei are formed from mis-segregation of chromosomes during mitosis 13 . Recently, cGAS was found to promote micronuclei formation and cell death in respond to DNA damage 30 . It is possible that the chromosomal localization of cGAS in mitotic cells contributes to eradication of cells with damaged genomes.…”

Nuclear innate sensors for nucleic acids in immunity and inflammation

“…While cGAS is more recently shown to be able to translocate from the cytoplasm to the nucleus and is possibly involved in DNA repair and mitosis by associating with chromatin. [39][40][41] These studies provide a new perspective to explore the spatiotemporal activation of innate sensors.…”

“…[103][104][105][106] Some cytoplasmic sensors, such as cGAS and AIM2, have recently been found to translocate to the nucleus and are recruited to chromatin double-stranded breaks (DSBs) or initiate inflammatory response after DNA damage. 40,41,105 In addition, accumulating evidence indicates that DNA damage and repair machinery and DNA damage response (DDR) sensors are also involved in pathogen invasion. Various DNA viruses hijack host DDR and DNA repair components to facilitate viral genome replication during viral infection.…”

Cytolethal Distending Toxin: from mitotic DNA damage to cGAS-dependent pro-inflammatory response

“…Altogether, these results unravel the essential role of cGAS during CDT intoxination through MN recognition, eliciting cell distention, senescence and pro-inflammatory responses. However, we cannot exclude that in CDT-exposed cells, cGAS inhibits DSB repair and/or promotes mitotic cell death upon retardation of metaphase-anaphase transition [39,40], therefore participating in the sensitivity to the toxin. Persistent infection causes chronic inflammation, a driving force of tumor development [41].…”