van der Sluijs, R.V., Verkennis, A.E.E., Hodskinson, M.R. et al. (17 more authors) (2025) DNA polymerase kappa is the primary translesion synthesis polymerase for aldehyde ICLs. Nucleic Acids Research, 53 (18). gkaf875. ISSN: 0305-1048
Abstract
DNA interstrand crosslinks (ICLs) are highly cytotoxic lesions that block essential cellular processes like replication and transcription. Endogenous ICLs can be induced by reactive aldehydes produced during normal cellular metabolism. Defective repair of these aldehyde-induced ICLs is associated with Fanconi anaemia (FA), a cancer predisposition syndrome. We previously showed that acetaldehyde-induced ICLs are repaired by the FA pathway and a novel excision-independent pathway. Here, we demonstrate that ICLs induced by acrolein, another cellular aldehyde, are also repaired by both pathways, establishing the generality of aldehyde ICL repair. Focusing on the FA pathway, we identify DNA polymerase kappa (Polκ) as the primary translesion synthesis (TLS) polymerase responsible for the insertion step during lesion bypass of unhooked aldehyde ICLs. This function requires Polκ’s catalytic activity and PCNA interaction domains but is independent of Rev1 interaction. In contrast, Polκ has a non-catalytic role in the extension step of cisplatin ICL repair that is dependent on Rev1 interaction. Our work reveals a key role for Polκ in aldehyde ICL repair and provides mechanistic insights into how different ICL structures determine the choice of TLS polymerases during repair.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://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. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. |
Keywords: | DNA-Directed DNA Polymerase; DNA Repair; Humans; Nucleotidyltransferases; DNA Damage; Aldehydes; Acrolein; Fanconi Anemia; Proliferating Cell Nuclear Antigen; Cisplatin; Translesion DNA Synthesis |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Mathematical and Physical Sciences The University of Sheffield > Faculty of Science (Sheffield) > Department of Chemistry (Sheffield) |
Date Deposited: | 06 Oct 2025 11:40 |
Last Modified: | 06 Oct 2025 11:40 |
Status: | Published |
Publisher: | Oxford University Press (OUP) |
Refereed: | Yes |
Identification Number: | 10.1093/nar/gkaf875 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:232571 |