DNA polymerase kappa is the primary translesion synthesis polymerase for aldehyde ICLs

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.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-09-23
DOI
https://doi.org/10.1093/nar/gkaf875
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

DNA polymerase kappa is the primary translesion synthesis polymerase for aldehyde ICLs

Sally B. Morton, M.R.G. Hodskinson, Miguel Hernández-Quiles, Maarten Altelaar et al.
Nucleic Acids Research
DNA Repair Mechanisms
article

DNA polymerase kappa is the primary translesion synthesis polymerase for aldehyde ICLs

Sally B. Morton, M.R.G. Hodskinson, Miguel Hernández-Quiles, Maarten Altelaar, Francesca Mattiroli, Harm Post, Jamie Barnett, Alexander E. E. Verkennis, Christopher L. Millington, Michiel Vermeulen, David M. Williams, Giulia Ricci, Aiko Hendrikx, Puck Knipscheer, Clément Rouillon, Ketan J. Patel, Themistoklis Liolios, Victoria M. Cruz, C.J. Bos, Roxanne V van der Sluijs
article en

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.

Nucleic Acids ResearchVol. 53(18)
Radboud University Nijmegen (NL), MRC Laboratory of Molecular Biology (GB), Utrecht University (NL), Leiden University Medical Center (NL), Radboud University Medical Center (NL), The Netherlands Cancer Institute (NL), University Medical Center Utrecht (NL), Abterra Biosciences (United States) (US), Netherlands Metabolomics Centre (NL), Radboud Institute for Molecular Life Sciences (NL), Oncode Institute (NL), Hubrecht Institute for Developmental Biology and Stem Cell Research (NL), Cancer Genomics Centre (NL), Cancer Genetics (United States) (US), University of Sheffield (GB)
Nederlandse Organisatie voor Wetenschappelijk Onderzoek, KWF Kankerbestrijding, Oncode Institute
Openalex Percentile: Top 77%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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