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 () and Puck Knipscheer ()
Additional contact information
Michael R. Hodskinson: MRC Laboratory of Molecular Biology
Alice Bolner: Hubrecht Institute–KNAW and University Medical Center Utrecht
Koichi Sato: Hubrecht Institute–KNAW and University Medical Center Utrecht
Ashley N. Kamimae-Lanning: MRC Laboratory of Molecular Biology
Koos Rooijers: Hubrecht Institute–KNAW and University Medical Center Utrecht
Merlijn Witte: Hubrecht Institute–KNAW and University Medical Center Utrecht
Mohan Mahesh: MRC Laboratory of Molecular Biology
Jan Silhan: MRC Laboratory of Molecular Biology
Maya Petek: MRC Laboratory of Molecular Biology
David M. Williams: The University of Sheffield
Jop Kind: Hubrecht Institute–KNAW and University Medical Center Utrecht
Jason W. Chin: MRC Laboratory of Molecular Biology
Ketan J. Patel: MRC Laboratory of Molecular Biology
Puck Knipscheer: Hubrecht Institute–KNAW and University Medical Center Utrecht

Nature, 2020, vol. 579, issue 7800, 603-608

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2059-5

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