Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells.

Authors:
Juan I Garaycoechea
Juan I Garaycoechea
MRC Laboratory of Molecular Biology
United Kingdom
Gerry P Crossan
Gerry P Crossan
MRC Laboratory of Molecular Biology
Fentang Yang
Fentang Yang
Addenbrooke's Hospital
United Kingdom
Guillaume Guilbaud
Guillaume Guilbaud
Université de Lyon
France
Naomi Park
Naomi Park
Wellcome Trust Sanger Institute

Nature 2018 01 3;553(7687):171-177. Epub 2018 Jan 3.

MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.

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.

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Source
http://www.nature.com/doifinder/10.1038/nature25154
Publisher Site
http://dx.doi.org/10.1038/nature25154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047743PMC
January 2018
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(Supplied by CrossRef)
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J. Prev. Med. Public Health 2015
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Chem. Res. Toxicol. 2000
Article in Alcohol. Clin. Exp. Res.
CL Lai et al.
Alcohol. Clin. Exp. Res. 2014
Article in Jpn. J. Clin. Oncol.
A Yokoyama et al.
Jpn. J. Clin. Oncol. 2003
Article in Nature
JI Garaycoechea et al.
Nature 2012
Article in Nature
F Langevin et al.
Nature 2011
Article in Blood
JI Garaycoechea et al.
Blood 2014
Article in Blood
A Hira et al.
Blood 2013
Article in Nature
A Nijnik et al.
Nature 2007
Article in Nature
DJ Rossi et al.
Nature 2007
Article in Cell Stem Cell
M Milyavsky et al.
Cell Stem Cell 2010

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