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Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Author

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  • Frédéric Langevin

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Gerry P. Crossan

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Ivan V. Rosado

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK)

  • Mark J. Arends

    (University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK)

  • Ketan J. Patel

    (MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
    University of Cambridge, Level 5, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK)

Abstract

Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2−/− embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2+/− ) can support the development of double-mutant (Aldh2−/−Fancd2−/− ) mice. However, these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2−/−Fancd2−/− mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients.

Suggested Citation

  • Frédéric Langevin & Gerry P. Crossan & Ivan V. Rosado & Mark J. Arends & Ketan J. Patel, 2011. "Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice," Nature, Nature, vol. 475(7354), pages 53-58, July.
    • Handle: RePEc:nat:nature:v:475:y:2011:i:7354:d:10.1038_nature10192
    DOI: 10.1038/nature10192
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    Cited by:

    1. Yuandi Gao & Laure Guitton-Sert & Julien Dessapt & Yan Coulombe & Amélie Rodrigue & Larissa Milano & Andréanne Blondeau & Nicolai Balle Larsen & Julien P. Duxin & Samer Hussein & Amélie Fradet-Turcott, 2023. "A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Yi-Cheng Chang & Hsiao-Lin Lee & Wenjin Yang & Meng-Lun Hsieh & Cai-Cin Liu & Tung-Yuan Lee & Jing-Yong Huang & Jiun-Yi Nong & Fu-An Li & Hsiao-Li Chuang & Zhi-Zhong Ding & Wei-Lun Su & Li-Yun Chueh &, 2023. "A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Sebastian M. Siegner & Laura Ugalde & Alexandra Clemens & Laura Garcia-Garcia & Juan A. Bueren & Paula Rio & Mehmet E. Karasu & Jacob E. Corn, 2022. "Adenine base editing efficiently restores the function of Fanconi anemia hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Karl-Heinz Tomaszowski & Sunetra Roy & Carolina Guerrero & Poojan Shukla & Caezaan Keshvani & Yue Chen & Martina Ott & Xiaogang Wu & Jianhua Zhang & Courtney D. DiNardo & Detlev Schindler & Katharina , 2023. "Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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