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Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin

Bacolla, Albino, Sengupta, Shiladitya, Ye, Zu, Yang, Chunying, Mitra, Joy, De-Paula, Ruth B, Hegde, Muralidhar L, Ahmed, Zamal, Mort, Matthew, Cooper, David N, Mitra, Sankar and Tainer, John A 2021. Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin. Nucleic Acids Research 49 (1) , pp. 221-243. 10.1093/nar/gkaa1120

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Abstract

Human genome stability requires efficient repair of oxidized bases, which is initiated via damage recognition and excision by NEIL1 and other base excision repair (BER) pathway DNA glycosylases (DGs). However, the biological mechanisms underlying detection of damaged bases among the million-fold excess of undamaged bases remain enigmatic. Indeed, mutation rates vary greatly within individual genomes, and lesion recognition by purified DGs in the chromatin context is inefficient. Employing super-resolution microscopy and co-immunoprecipitation assays, we find that acetylated NEIL1 (AcNEIL1), but not its non-acetylated form, is predominantly localized in the nucleus in association with epigenetic marks of uncondensed chromatin. Furthermore, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed non-random AcNEIL1 binding near transcription start sites of weakly transcribed genes and along highly transcribed chromatin domains. Bioinformatic analyses revealed a striking correspondence between AcNEIL1 occupancy along the genome and mutation rates, with AcNEIL1-occupied sites exhibiting fewer mutations compared to AcNEIL1-free domains, both in cancer genomes and in population variation. Intriguingly, from the evolutionarily conserved unstructured domain that targets NEIL1 to open chromatin, its damage surveillance of highly oxidation-susceptible sites to preserve essential gene function and to limit instability and cancer likely originated ∼500 million years ago during the buildup of free atmospheric oxygen.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Publisher: Oxford University Press
ISSN: 0305-1048
Date of First Compliant Deposit: 18 December 2020
Date of Acceptance: 7 December 2020
Last Modified: 30 Jan 2022 10:13
URI: https://orca.cardiff.ac.uk/id/eprint/137112

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