Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Michael R Hodskinson, Alice Bolner, Koichi Sato, Ashley N Kamimae-Lanning, Koos Rooijers, Merlijn Witte, Mohan Mahesh, Jan Silhan, Maya Petek, David M Williams, Jop Kind, Jason W Chin, Ketan J Patel, Puck Knipscheer

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5-7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision-analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions-instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.

Original languageEnglish
Pages (from-to)603-608
Number of pages6
JournalNature
Volume579
Issue number7800
DOIs
Publication statusPublished - Mar 2020

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    Hodskinson, M. R., Bolner, A., Sato, K., Kamimae-Lanning, A. N., Rooijers, K., Witte, M., Mahesh, M., Silhan, J., Petek, M., Williams, D. M., Kind, J., Chin, J. W., Patel, K. J., & Knipscheer, P. (2020). Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms. Nature, 579(7800), 603-608. https://doi.org/10.1038/s41586-020-2059-5