Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function

MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Nature (Impact Factor: 41.46). 08/2012; 489(7417):571-5. DOI: 10.1038/nature11368
Source: PubMed


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. 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. 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. 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.

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    • "−/− mice on chronic ethanol treatment from acetaldehyde-induced damage to the hematopoietic system It has recently been shown that aldehyde toxicity in hematopoietic stem cells contributes to stem cell depletion in FA patients and mouse models (Garaycoechea et al., 2012; "

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    • "DNA ICLs are deleterious DNA lesions that covalently link DNA strands blocking transcription and replication. Compounds such as mitomycin C (MMC), diepoxybutane (DEB), cisplatin, and nitrogen mustards can generate ICLs, whereas naturally occurring biological metabolites such as aldehydes are suspected to cause endogenous lesions (Garaycoechea et al., 2012; Hira et al., 2013; Langevin et al., 2011; Ridpath et al., 2007). Diagnosis of FA is made based on chromosomal breakage assays using crosslinking agents DEB or MMC (Auerbach, 1993). "
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    ABSTRACT: Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 06/2015; 12(1). DOI:10.1016/j.celrep.2015.06.014 · 8.36 Impact Factor
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    • "This is due to an accumulation of DNA lesions resulting in an overstimulation of DNA damage checkpoint responses in HSCs and their progenitors (Ceccaldi et al., 2012). Interestingly, lack of ICL repair recently was shown to sensitize murine HSCs to damage caused by endogenous aldehydes (Garaycoechea et al., 2012). In addition to the data on the requirement of ICL repair for stem cell maintenance, studies on mice deficient for nucleotide excision repair demonstrate a critical role also for this pathway in HSC maintenance and prevention of premature ageing (Fig. 2; Rossi et al., 2007a). "
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    ABSTRACT: The mammalian organism is comprised of tissue types with varying degrees of self-renewal and regenerative capacity. In most organs self-renewing tissue-specific stem and progenitor cells contribute to organ maintenance, and it is vital to maintain a functional stem cell pool to preserve organ homeostasis. Various conditions like tissue injury, stress responses, and regeneration challenge the stem cell pool to re-establish homeostasis (Figure 1). However, with increasing age the functionality of adult stem cells declines and genomic mutations accumulate. These defects affect different cellular response pathways and lead to impairments in regeneration, stress tolerance, and organ function as well as to an increased risk for the development of ageing associated diseases and cancer. Maintenance of the genome appears to be of utmost importance to preserve stem cell function and to reduce the risk of ageing associated dysfunctions and pathologies. In this review, we discuss the causal link between stem cell dysfunction and DNA damage accrual, different strategies how stem cells maintain genome integrity, and how these processes are affected during ageing.
    Ageing Research Reviews 02/2015; 102(Pt A). DOI:10.1016/j.arr.2015.01.004 · 4.94 Impact Factor
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