Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells

Juan I. Garaycoechea, Gerry P. Crossan, Frédéric Langevin, Lee Mulderrig, Sandra Louzada, Fentang Yang, Guillaume Guilbaud, Naomi Park, Sophie Roerink, Serena Nik-Zainal, Michael R. Stratton and Ketan J. Patel ()
Additional contact information
Juan I. Garaycoechea: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue
Gerry P. Crossan: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue
Frédéric Langevin: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue
Lee Mulderrig: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue
Sandra Louzada: Wellcome Trust Sanger Institute, Hinxton
Fentang Yang: Wellcome Trust Sanger Institute, Hinxton
Guillaume Guilbaud: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue
Naomi Park: Wellcome Trust Sanger Institute, Hinxton
Sophie Roerink: Wellcome Trust Sanger Institute, Hinxton
Serena Nik-Zainal: Wellcome Trust Sanger Institute, Hinxton
Michael R. Stratton: Wellcome Trust Sanger Institute, Hinxton
Ketan J. Patel: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue

Nature, 2018, vol. 553, issue 7687, 171-177

Abstract: Abstract Haematopoietic stem cells renew blood. Accumulation of DNA damage in these cells promotes their decline, while misrepair of this damage initiates malignancies. Here we describe the features and mutational landscape of DNA damage caused by acetaldehyde, an endogenous and alcohol-derived metabolite. This damage results in DNA double-stranded breaks that, despite stimulating recombination repair, also cause chromosome rearrangements. We combined transplantation of single haematopoietic stem cells with whole-genome sequencing to show that this damage occurs in stem cells, leading to deletions and rearrangements that are indicative of microhomology-mediated end-joining repair. Moreover, deletion of p53 completely rescues the survival of aldehyde-stressed and mutated haematopoietic stem cells, but does not change the pattern or the intensity of genome instability within individual stem cells. These findings characterize the mutation of the stem-cell genome by an alcohol-derived and endogenous source of DNA damage. Furthermore, we identify how the choice of DNA-repair pathway and a stringent p53 response limit the transmission of aldehyde-induced mutations in stem cells.

Date: 2018
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DOI: 10.1038/nature25154

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