Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms
- 1 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 579 (7800), 603-+
- https://doi.org/10.1038/s41586-020-2059-5
Abstract
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.This publication has 24 references indexed in Scilit:
- Alcohol and endogenous aldehydes damage chromosomes and mutate stem cellsNature, 2018
- What is the DNA repair defect underlying Fanconi anemia?Current Opinion in Cell Biology, 2015
- Why does the bone marrow fail in Fanconi anemia?Blood, 2014
- Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patientsBlood, 2013
- Dominance of the Inactive Asian Variant Over Activity and Protein Contents of Mitochondrial Aldehyde Dehydrogenase 2 in Human LiverAlcohol: Clinical and Experimental Research, 2013
- Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell functionNature, 2012
- Fancd2 counteracts the toxic effects of naturally produced aldehydes in miceNature, 2011
- The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol ConsumptionPLoS Medicine, 2009
- Stereospecific Formation of Interstrand Carbinolamine DNA Cross-Links by Crotonaldehyde- and Acetaldehyde-Derived α-CH3-γ-OH-1,N2-Propano-2‘-deoxyguanosine Adducts in the 5‘-CpG-3‘ SequenceChemical Research in Toxicology, 2005
- Identification of DNA Adducts of AcetaldehydeChemical Research in Toxicology, 2000