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Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells

Nature (London), 2018-01, Vol.553 (7687), p.171-177 [Peer Reviewed Journal]

COPYRIGHT 2018 Nature Publishing Group ;COPYRIGHT 2018 Nature Publishing Group ;Copyright Nature Publishing Group Jan 11, 2018 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/nature25154 ;PMID: 29323295

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Title:
Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells
Author: Garaycoechea, Juan I ; Crossan, Gerry P ; Langevin, Frédéric ; Mulderrig, Lee ; Louzada, Sandra ; Yang, Fentang ; Guilbaud, Guillaume ; Park, Naomi ; Roerink, Sophie ; Nik-Zainal, Serena ; Stratton, Michael R ; Patel, Ketan J
Subjects: Acetaldehyde ; Acetaldehyde - metabolism ; Alcohol ; Alcohol Dehydrogenase - deficiency ; Alcohol Dehydrogenase - genetics ; Alcohol Dehydrogenase - metabolism ; Alcoholic beverages ; Alcohols ; Aldehydes ; Animals ; Cell cycle ; Cell survival ; Cell Survival - drug effects ; Chromosome rearrangements ; Chromosomes ; Clonal deletion ; Damage accumulation ; Dehydrogenases ; Deoxyribonucleic acid ; DNA ; DNA Breaks, Double-Stranded - drug effects ; DNA damage ; DNA End-Joining Repair ; DNA repair ; Ethanol ; Ethanol - administration & dosage ; Ethanol - metabolism ; Ethanol - pharmacology ; Fanconi Anemia - genetics ; Fanconi Anemia - metabolism ; Fanconi Anemia - pathology ; Fanconi Anemia Complementation Group D2 Protein - deficiency ; Fanconi Anemia Complementation Group D2 Protein - genetics ; Fanconi Anemia Complementation Group D2 Protein - metabolism ; Female ; Gene Deletion ; Gene sequencing ; Genes, p53 - genetics ; Genomes ; Genomic instability ; Genomic Instability - drug effects ; Health aspects ; Hematopoietic Stem Cell Transplantation ; Hematopoietic stem cells ; Hematopoietic Stem Cells - drug effects ; Hematopoietic Stem Cells - metabolism ; Hematopoietic Stem Cells - pathology ; Ku Autoantigen - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mutagenesis ; Mutation ; p53 Protein ; Recombination ; Recombinational DNA Repair - drug effects ; Stem cells ; Transplantation ; Tumor Suppressor Protein p53 - deficiency ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Whole Genome Sequencing
Is Part Of: Nature (London), 2018-01, Vol.553 (7687), p.171-177
Description: 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.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/nature25154
PMID: 29323295
Source: ProQuest One Psychology
AUTh Library subscriptions: ProQuest Central
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Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells

COPYRIGHT 2018 Nature Publishing Group ;COPYRIGHT 2018 Nature Publishing Group ;Copyright Nature Publishing Group Jan 11, 2018 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/nature25154 ;PMID: 29323295

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