A Mechanism for Oxidative Damage Repair at Gene Regulatory Elements

Overview

Journal Nature

Specialty Science

Date 2022 Sep 28

PMID 36171374

Authors

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

Sherif F El-Khamisy

Affiliations

Soon will be listed here.

Abstract

Oxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional activation. 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.

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