期刊
MOLECULAR CELL
卷 60, 期 1, 页码 177-188出版社
CELL PRESS
DOI: 10.1016/j.molcel.2015.08.020
关键词
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资金
- Medical Research Council [MC_U105178811]
- ISCIII [CP12/03273]
- Spanish Ministry of Economy and Competitiveness [BFU2013-041457-P]
- NIEHS [P42 ES005948, P30 ES010126]
- Texas Commission for Environmental Quality [582-12-21861]
- CRUK
- Wellcome Trust
- Medical Research Council
- MRC [MC_U105178811] Funding Source: UKRI
- Cancer Research UK [13647] Funding Source: researchfish
- Medical Research Council [MC_U105178811] Funding Source: researchfish
Endogenous formaldehyde is produced by numerous biochemical pathways fundamental to life, and it can crosslink both DNA and proteins. However, the consequences of its accumulation are unclear. Here we show that endogenous formaldehyde is removed by the enzyme alcohol dehydrogenase 5 (ADH5/ GSNOR), and Adh5(-I-) mice therefore accumulate formaldehyde adducts in DNA. The repair of this damage is mediated by FANCD2, a DNA crosslink repair protein. Adh5(-I-)Fancd2(-I-) mice reveal an essential requirement for these protection mechanisms in hematopoietic stem cells (HSCs), leading to their depletion and precipitating bone marrow failure. More widespread formaldehyde-induced DNA damage also causes karyomegaly and dysfunction of hepatocytes and nephrons. Bone marrow transplantation not only rescued hematopoiesis but, surprisingly, also preserved nephron function. Nevertheless, all of these animals eventually developed fatal malignancies. Formaldehyde is therefore an important source of endogenous DNA damage that is counteracted in mammals by a conserved protection mechanism.
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