A mechanism for oxidative damage repair at gene regulatory elements

Ray, Swagat, Abugable, Arwa A., Parker, Jacob , Liversidge, Kirsty, Palminha, Nelma M., Liao, Chunyan, Acosta-Martin, Adelina E., Souza, Cleide D. S., Jurga, Mateusz, Sudbery, Ian and El-Khamisy, Sherif F. (2022) A mechanism for oxidative damage repair at gene regulatory elements. Nature, 609 . pp. 1038-1047. ISSN 0028-0836

Full content URL: https://doi.org/10.1038/s41586-022-05217-8

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Abstract

Oxidative 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 fulfilling this function.

Keywords:DNA damage response, Oxidative stress, gene transcription, Gene Expression Data, Proteomics
Subjects:C Biological Sciences > C130 Cell Biology
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
C Biological Sciences > C100 Biology
Divisions:College of Science > School of Life and Environmental Sciences > Department of Life Sciences
ID Code:51942
Deposited On:11 Oct 2022 09:39

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