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Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells

Author

Listed:
  • 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
    University of Cambridge, Addenbrooke’s Hospital, Hills Rd)

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.

Suggested Citation

  • 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, 2018. "Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells," Nature, Nature, vol. 553(7687), pages 171-177, January.
    • Handle: RePEc:nat:nature:v:553:y:2018:i:7687:d:10.1038_nature25154
    DOI: 10.1038/nature25154
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    Cited by:

    1. Ross J. Hill & Nazareno Bona & Job Smink & Hannah K. Webb & Alastair Crisp & Juan I. Garaycoechea & Gerry P. Crossan, 2024. "p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Yan Yan & Hui Liu & Canfei He, 2021. "How Does Urban Sprawl Affect Public Health? Evidence from Panel Survey Data in Urbanizing China," IJERPH, MDPI, vol. 18(19), pages 1-14, September.
    3. Meredith Packer & Dipendra Gyawali & Ravikiran Yerabolu & Joseph Schariter & Phil White, 2021. "A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Hye Kyung Kim & Rachel Lim Si En & Dorothy Wong Kang Min, 2019. "Psychosocial Motivators for Moderate Drinking among Young Asian Flushers in Singapore," IJERPH, MDPI, vol. 16(11), pages 1-12, May.
    5. Carla Umansky & Agustín E. Morellato & Matthias Rieckher & Marco A. Scheidegger & Manuela R. Martinefski & Gabriela A. Fernández & Oleg Pak & Ksenia Kolesnikova & Hernán Reingruber & Mariela Bollini &, 2022. "Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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