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dc.contributor.authorSwagat, R.
dc.contributor.authorAbugable, A.A.
dc.contributor.authorParker, J.
dc.contributor.authorLiversidge, K.
dc.contributor.authorPalminha, N.M.
dc.contributor.authorLiao, C.
dc.contributor.authorAcosta-Martin, A.E.
dc.contributor.authorSouza, C.D.S.
dc.contributor.authorJurga, Mateusz
dc.contributor.authorSudbery, I.
dc.contributor.authorEl-Khamisy, Sherif
dc.date.accessioned2023-11-01T15:00:20Z
dc.date.accessioned2023-11-10T09:49:48Z
dc.date.available2023-11-01T15:00:20Z
dc.date.available2023-11-10T09:49:48Z
dc.date.issued2022-09-29
dc.identifier.citationSwagat R, Abugable AA, Parker J et al (2022) A mechanism for oxidative damage repair at gene regulatory elements. Nature. 609(7929): 1038-1047.
dc.identifier.urihttp://hdl.handle.net/10454/19670
dc.descriptionYes
dc.description.abstractOxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional activation1,2. Here we show that promoters are protected from oxidative damage via a process mediated by the nuclear mitotic apparatus protein NuMA (also known as NUMA1). NuMA exhibits genomic occupancy approximately 100 bp around transcription start sites. It binds the initiating form of RNA polymerase II, pause-release factors and single-strand break repair (SSBR) components such as TDP1. The binding is increased on chromatin following oxidative damage, and TDP1 enrichment at damaged chromatin is facilitated by NuMA. Depletion of NuMA increases oxidative damage at promoters. NuMA promotes transcription by limiting the polyADP-ribosylation of RNA polymerase II, increasing its availability and release from pausing at promoters. Metabolic labelling of nascent RNA identifies genes that depend on NuMA for transcription including immediate-early response genes. Complementation of NuMA-deficient cells with a mutant that mediates binding to SSBR, or a mitotic separation-of-function mutant, restores SSBR defects. These findings underscore the importance of oxidative DNA damage repair at gene regulatory elements and describe a process that fulfils this function.
dc.language.isoen
dc.rights(C) 2022 SpringerNature. Full-text reproduced in accordance with the publisher's self-archiving policy.
dc.subjectAlzheimer's Disease
dc.subjectCancer genomics
dc.subjectGenetics research
dc.subjectSingle-strand DNA breaks
dc.subjectTranscriptional regulatory elements
dc.titleA mechanism for oxidative damage repair at gene regulatory elements
dc.status.refereedYes
dc.date.Accepted2022-08-09
dc.date.application2022-09-28
dc.typeArticle
dc.type.versionAccepted manuscript
dc.identifier.doihttps://doi.org/10.1038/s41586-022-05217-8
dc.rights.licenseUnspecified
dc.date.updated2023-11-01T15:00:26Z
refterms.dateFOA2023-11-10T09:50:08Z
dc.openaccess.statusopenAccess


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