March-April 2018, Volume 15, Issue 2
Complexity of DNA Repair From Alcohol Damage Revealed
Published on: February 07, 2018
Garaycoechea JI, Crossan GP, Langevin F, et al. Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells. Nature. 2018;553:171-177.
Hematologists have long known of alcohol’s negative effects on blood cells and hematopoiesis — effects that were thought to be reversible.1,2 However, is the latter strictly true? While alcohol is not typically listed as an environmental agent causing hematologic malignancies, it is metabolized to acetaldehyde, a carcinogen that damages DNA, and chronic alcohol use is certainly associated with solid tumors, including breast, liver, colon, and esophageal.3 Indeed, an insidious action of alcohol on the bone marrow was revealed when Japanese patients with Fanconi anemia (FA) and elevated acetaldehyde from aldehyde dehydrogenase 2 (ALDH2) deficiency were found to have an accelerated progression to bone marrow failure.4 However, the interplay between alcohol, acetaldehyde, DNA damage, and its subsequent repair in hematopoietic stem cells (HSCs) has not been well understood until now.
In a recent Nature article, Dr. Juan I. Garaycoechea and colleagues found that acetaldehyde damages the DNA of mouse bone marrow HSCs, and its correction requires multiple different mechanisms of DNA repair. A wealth of prior research has taught us that the FA repair pathway protects against cumulative DNA cross-link damage. By studying patients with this rare disease and through experiments on the different FA genes, we know that this pathway is complex and involves very different DNA repair mechanisms including homologous recombination, nucleotide excision repair, and translesion synthesis. The authors previously looked at mice with a strong FA phenotype.5 The mice lack FANCD2, an important FA protein involved in the recruitment of downstream DNA repair. When these mice were also deficient in aldehyde dehydrogenase 2 (Aldh2-/-Fancd2-/-), the HSCs were more susceptible to acetaldehyde.
Now in an elegant series of sequential genetic deletion experiments, the authors have defined which of the DNA repair mechanisms are needed to protect from acetaldehyde-induced DNA damage. First, they showed that Aldh2-/-Fancd2-/- mouse bone marrow cells had chromosomes with increased reciprocal transfer of genetic material between sister chromatids. This phenomenon, known as sister chromatid exchange, is often used as a surrogate marker for homologous recombination events. The number of sister chromatid exchanges is potentiated on exposure to alcohol and indicated that acetaldehyde induces homologous recombination DNA repair. They then confirmed this by showing that DT40 cells lacking both homologous recombination and FA genes were more sensitive to acetaldehyde than cells deficient in only one.
Next, they used micronuclei in enucleated erythrocytes and multiplex FISH as markers for DNA damage. In Aldh2-/-Fancd2-/- mice, there is a basal increase in DNA damage, and this was exacerbated fourfold by exposure to ethanol. This shows that in the presence of normally functioning homologous recombination repair machinery, the FA pathway is also required to repair chromosome breakage from acetaldehyde. They then looked at mice lacking the FA repair gene Fanca and the nonhomologous end-joining repair (NHEJ) protein Ku70. These mice were anemic, had fewer HSCs, had more DNA damage, and were more sensitive to acetaldehyde. This suggested that NHEJ repair is also important for repair of acetaldehyde-induced DNA damage, at least in the absence of the FA pathway.
Finally, serial transplantation experiments with either one or five HSCs showed that Aldh2-/-Fancd2-/- mice have HSCs that are less able to engraft and contribute to hematopoiesis in recipient mice. By sequencing the recipient mouse bone marrows, they showed that acetaldehyde causes specific structural DNA damage involving insertions, deletions, translocations,and rearrangements. Aldh2-/-Fancd2-/- mice also had hematopoietic and progenitor stem cells with increased expression of p53 and the poor bone marrow engraftment improved on a p53 null background.
In summary, Dr. Garaycoechea and colleagues have provided us with further insight into the types of DNA damage wrought by alcohol and the different mechanisms required to repair them. If unrepaired, alcohol-induced DNA damage has long-term deleterious effects on the function of mouse hematopoiesis, particularly when abnormalities in DNA repair are present. This explains the clinical findings in patients with FA carrying negative variants of ALDH2. It also has broader implications for understanding the toxic effects of alcohol in both nonhematopoietic cells and HSCs, and for the 540 million people worldwide who are deficient in aldehyde dehydrogenase.3
Ballard HS. The hematological complications of alcoholism. Alcohol Health Res World. 1997;21:42-52.
Nakao S, Harada M, Kondo K, et al. Reversible bone marrow hypoplasia induced by alcohol. Am J Hematol. 1991;37:120-123.
Brooks PJ, Enoch MA, Goldman D, et al. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med. 2009;6:e50.
Hira A, Yabe H, Yoshida K, et al. Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients. Blood. 2013;122:3206-3209.
Garaycoechea JI, Crossan GP, Langevin F, et al. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature. 2012;489:571-575.
Conflict of Interests
Dr. Chew and Dr. Roberts indicated no relevant conflicts of interest.
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