Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

被引：391

作者：

Langevin, Frederic ^{[1
]}

Crossan, Gerry P. ^{[1
]}

Rosado, Ivan V. ^{[1
]}

Arends, Mark J. ^{[2
]}

Patel, Ketan J. ^{[1
,3
]}

机构：

[1] MRC Lab Mol Biol, Cambridge CB2 0QH, England

[2] Univ Cambridge, Addenbrookes Hosp, Dept Pathol, Cambridge CB2 2QQ, England

[3] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 0QQ, England

来源：

NATURE | 2011年 / 475卷 / 7354期

关键词：

FETAL ALCOHOL SYNDROME; FANCONI-ANEMIA; DNA-ADDUCTS; CHILDHOOD LEUKEMIA; KNOCKOUT MICE; BONE-MARROW; ACETALDEHYDE; ETHANOL; CONSUMPTION; METABOLISM;

D O I：

10.1038/nature10192

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 metabolished 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 usually 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.

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页码：53 / U67

页数：7

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