Chromatin-bound cGAS is an Inhibitor of DNA Repair and Hence Accelerates Genome Destabilization and Cell Death

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dc.contributor.authorJiang, Hui
dc.contributor.authorXue, Xiaoyu
dc.contributor.authorPanda, Swarupa
dc.contributor.authorKawale, Ajinkya
dc.contributor.authorHooy, Richard M.
dc.contributor.authorLiang, Fengshan
dc.contributor.authorSohn, Jungsan
dc.contributor.authorSung, Patrick
dc.contributor.authorGekara, Nelson O.
dc.date.accessioned2019-10-01T18:44:18Z
dc.date.available2019-10-01T18:44:18Z
dc.date.issued2019-01
dc.description.abstractDNA 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.
dc.description.departmentChemistry and Biochemistry
dc.formatText
dc.format.extent17 pages
dc.format.medium1 file (.pdf)
dc.identifier.citationJiang, H., Xue, X., Panda, S., Kawale, A., Hooy, R. M., Liang, F., Sohn, J., Sung, P., Sung, P., & Gekara, N. O. (2019). Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death. The EMBO Journal, 2019, e102718.
dc.identifier.doihttps://doi.org/10.15252/embj.2019102718
dc.identifier.urihttps://hdl.handle.net/10877/8658
dc.language.isoen
dc.publisherEMBO Press
dc.rights.holder© 2019 The Authors.
dc.rights.licenseThis work is licensed under a Creative Commons Attribution 4.0 International License.
dc.sourceThe EMBO Journal, 2019, Article e102718
dc.subjectcell death
dc.subjectcGAS
dc.subjectchromatin compaction
dc.subjectDNA repair
dc.subjectDNA Replication
dc.subjectrepair and Recombination
dc.subjectimmunology
dc.subjectcancer
dc.subjectChemistry and Biochemistry
dc.titleChromatin-bound cGAS is an Inhibitor of DNA Repair and Hence Accelerates Genome Destabilization and Cell Death
dc.typeArticle

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