Journal
NATURE
Volume 579, Issue 7800, Pages 603-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2059-5
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Funding
- Dutch Cancer Society [KWF HUBR 2015-7736]
- Gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO), part of the Oncode Institute - Dutch Cancer Society
- Uehara Memorial Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- JSPS Postdoctoral Fellowship for Research Abroad
- Wellcome Trust
- Cancer Research UK
- European Research Council [ERC-STG 678423-EpiID]
- NWO Veni grant [016.Veni.181.013]
- MRC [MC_U105178811, MC_U105181009] Funding Source: UKRI
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Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption(1). Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers(1,2). 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 cancer(3,4). The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells(5-7). 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. DNA interstrand crosslinks induced by acetaldehyde are repaired by both the Fanconi anaemia pathway and by a second, excision-independent repair mechanism.
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