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Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0003-1170-0224
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0001-7622-5116
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2019 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, article id e102718Article in journal (Refereed) Epub ahead of print
Abstract [en]

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.

Place, publisher, year, edition, pages
EMBOpress , 2019. article id e102718
Keywords [en]
cancer, cell death, cGAS, chromatin compaction, DNA repair
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-164894DOI: 10.15252/embj.2019102718ISI: 000487392000001PubMedID: 31544964OAI: oai:DiVA.org:umu-164894DiVA, id: diva2:1368113
Funder
Swedish Research Council, 2015-02857Swedish Research Council, 2016-00890Swedish Cancer Society, CAN 2017/421NIH (National Institute of Health), R01 CA220123NIH (National Institute of Health), P30 CA054174NIH (National Institute of Health), R01 GM GM 129342-01-A1Available from: 2019-11-06 Created: 2019-11-06 Last updated: 2019-11-07

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Jiang, HuiPanda, SwarupaGekara, Nelson O.

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4546474849505148 of 245
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