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Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death
Author(s) -
Jiang Hui,
Xue Xiaoyu,
Panda Swarupa,
Kawale Ajinkya,
Hooy Richard M,
Liang Fengshan,
Sohn Jungsan,
Sung Patrick,
Gekara Nelson O
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102718
Subject(s) - biology , chromatin , dna , microbiology and biotechnology , genome , genetics , dna repair , gene
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 ds DNA into a higher‐ordered state less amenable to strand invasion by RAD 51‐coated ss DNA filaments. This previously unknown role of cGAS has implications for understanding its involvement in genome instability‐associated disorders including cancer.