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. Mechanistica

SUBMITTER: Jiang H 

PROVIDER: S-EPMC6826206 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature