A mechanism for oxidative damage repair at gene regulatory elements

Swagat Ray, Arwa A. Abugable, Jacob Parker, Kirsty Liversidge, Nelma M. Palminha, Chunyan Liao, Adelina E. Acosta-Martin, Cleide D. S. Souza, Mateusz Jurga, Ian Sudbery and Sherif F. El-Khamisy ()
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Swagat Ray: University of Sheffield
Arwa A. Abugable: University of Sheffield
Jacob Parker: University of Sheffield
Kirsty Liversidge: University of Sheffield
Nelma M. Palminha: University of Sheffield
Chunyan Liao: University of Sheffield
Adelina E. Acosta-Martin: University of Sheffield
Cleide D. S. Souza: University of Sheffield
Mateusz Jurga: University of Bradford
Ian Sudbery: University of Sheffield
Sherif F. El-Khamisy: University of Sheffield

Nature, 2022, vol. 609, issue 7929, 1038-1047

Abstract: 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 that fulfils this function.

Date: 2022
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DOI: 10.1038/s41586-022-05217-8

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