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Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
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Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
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Journal Article
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
2012
Overview
The function of haematopoietic stem and progenitor cells is impaired by damaged DNA; here, endogenously generated aldehydes are found to be one source of such damage, which is repaired by the Fanconi anaemia pathway.
Bone-marrow failure in Fanconi anaemia
Haematopoietic stem cells handle DNA-damage stress through enzymatic detoxification and DNA repair. Dismantling both protective mechanisms predisposes mice to leukaemia and susceptibility to exogenous aldehyde. Ketan Patel and colleagues now show that even if these mice escape leukaemia, they spontaneously develop features of Fanconi anaemia, such as aplastic anaemia and bone-marrow failure. The authors find that Aldh2 is the key enzyme protecting haematopoietic stem and progenitor cells from endogenous aldehyde toxicity. This genomic protection mechanism is dispensable in the more mature blood cells. These findings suggest that bone-marrow failure in Fanconi anaemia results from aldehyde-mediated genotoxicity in the haematopoietic stem- and progenitor-cell pool.
Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA
1
,
2
,
3
. However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes
4
,
5
. Mice with combined inactivation of aldehyde catabolism (through
Aldh2
knockout) and the Fanconi anaemia DNA-repair pathway (
Fancd2
knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol—an exogenous source of acetaldehyde
4
. Here we report that aged
Aldh2
−/−
Fancd2
−/−
mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require
Aldh2
for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Aging
/ Aldehyde Dehydrogenase - deficiency
/ Aldehyde Dehydrogenase - genetics
/ Aldehyde Dehydrogenase - metabolism
/ Aldehyde Dehydrogenase, Mitochondrial
/ Animals
/ DNA
/ Ethanol
/ Fanconi Anemia Complementation Group D2 Protein - deficiency
/ Fanconi Anemia Complementation Group D2 Protein - genetics
/ Female
/ Hematopoietic Stem Cells - cytology
/ Hematopoietic Stem Cells - drug effects
/ Hematopoietic Stem Cells - enzymology
/ Hematopoietic Stem Cells - metabolism
/ Humanities and Social Sciences
/ letter
/ Leukemia
/ Male
/ Mice
/ Science
