Author
Listed:
- 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
Imperial College London)
- Jan Silhan
(MRC Laboratory of Molecular Biology
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences)
- Maya Petek
(MRC Laboratory of Molecular Biology
University of Cambridge)
- 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
University of Oxford, John Radcliffe Hospital)
- Puck Knipscheer
(Hubrecht Institute–KNAW and University Medical Center Utrecht)
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.
Suggested Citation
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 &, 2020.
"Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms,"
Nature, Nature, vol. 579(7800), pages 603-608, March.
Handle:
RePEc:nat:nature:v:579:y:2020:i:7800:d:10.1038_s41586-020-2059-5
DOI: 10.1038/s41586-020-2059-5
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