Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Nature
Michael R HodskinsonPuck Knipscheer

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...Continue Reading

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Citations

Apr 30, 2020·Cell Research·Ravindra Amunugama, Johannes C Walter
Jul 1, 2020·International Journal of Molecular Sciences·Ekaterina ProshkinaAlexey Moskalev
Mar 27, 2020·Nature·Irene Gallina, Julien P Duxin
Aug 14, 2020·Cells·Radoslav AleksandrovAnastas Gospodinov
Jul 8, 2020·Nucleic Acids Research·Rachel Bezalel-BuchPeter M Burgers
Dec 16, 2020·Trends in Cell Biology·R Alex WuJohannes C Walter
Feb 9, 2021·Frontiers in Cell and Developmental Biology·Yeldar BaikenMurat Saparbaev
Feb 10, 2021·Seminars in Cell & Developmental Biology·Laure Guitton-SertJean-Yves Masson
Feb 5, 2021·Science Advances·Mohd MazeedRajan Sankaranarayanan
Feb 19, 2021·Critical Reviews in Biochemistry and Molecular Biology·Sarah J Young, Stephen C West
Aug 18, 2020·The Journal of Craniofacial Surgery·Jiankun CaoShuyan Qie
Mar 7, 2021·Biomolecules·Valeria GuidolinSilvia Balbo
Mar 12, 2021·The Journal of Craniofacial Surgery·Jiankun CaoShuyan Qie
Mar 12, 2021·Nucleic Acids Research·Mohamed Elsaid Ashour, Nima Mosammaparast
Apr 22, 2021·Molecular Cell·Arvind PandayRalph Scully
Apr 22, 2021·Annual Review of Biochemistry·Daniel R Semlow, Johannes C Walter
Sep 1, 2021·Cellular and Molecular Life Sciences : CMLS·Kazumasa Yoshida, Masatoshi Fujita
Aug 30, 2021·Molecular Cancer·Salvatore BenfattoBalca R Mardin
Sep 1, 2021·Current Opinion in Genetics & Development·Ralph ScullyNicholas A Willis
Sep 22, 2021·Carcinogenesis·Yuina SonoharaIsao Kuraoka
Nov 3, 2021·Journal of the American Chemical Society·Aaron L Rozelle, Seongmin Lee

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Methods Mentioned

BETA
electrophoresis
ubiquitination
PCR

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