Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast

Abstract

Acetaldehyde, a primary metabolite of alcohol, forms DNA adducts and disrupts the DNA replication process, causing genomic instability, a hallmark of cancer. Indeed, chronic alcohol consumption accounts for approximately 3.6% of all cancers worldwide. However, how the adducts are prevented and repaired after acetaldehyde exposure is not well understood. In this report, we used the fission yeast Schizosaccharomyces pombe as a model organism to comprehensively understand the genetic controls of DNA damage avoidance in response to acetaldehyde. We demonstrate that Atd1 functions as a major acetaldehyde detoxification enzyme that prevents accumulation of Rad52-DNA repair foci, while Atd2 and Atd3 have minor roles in acetaldehyde detoxification. We found that acetaldehyde causes DNA damage at the replication fork and activates the cell cycle checkpoint to coordinate cell cycle arrest with DNA repair. Our investigation suggests that acetaldehyde-mediated DNA adducts include interstrand-crosslinks and DNA-protein crosslinks. We also demonstrate that acetaldehyde activates multiple DNA repair pathways. Nucleotide excision repair and homologous recombination, which are both epistatically linked to the Fanconi anemia pathway, have major roles in acetaldehyde tolerance, while base excision repair and translesion synthesis also contribute to the prevention of acetaldehyde-dependent genomic instability. We also show the involvement of Wss1-related metalloproteases, Wss1 and Wss2, in acetaldehyde tolerance. These results indicate that acetaldehyde causes cellular stresses that require cells to coordinate multiple cellular processes in order to prevent genomic instability. Considering that acetaldehyde is a human carcinogen, our genetic studies serve as a guiding investigation into the mechanisms of acetaldehyde-dependent genomic instability and carcinogenesis.

Formation and repair of DNA-protein crosslink damage

“…Acetaldehyde, which is an intermediate in sugar metabolism as well as a key metabolite of ethanol, has also been demonstrated to react with the primary amines of DNA bases, yielding adducts of assorted chemical natures, including both DPCs and ICLs [Dellarco, 1988; Lorenti Garcia et al, 2009; Noguchi et al, 2017]. The nucleotide excision repair, homologous recombination, and Fanconi anemia pathways have each been shown to be important in the repair or prevention of DNA adducts formed by acetaldehyde, according to genetic studies in fission yeast [Noguchi et al, 2017].…”

“…The nucleotide excision repair, homologous recombination, and Fanconi anemia pathways have each been shown to be important in the repair or prevention of DNA adducts formed by acetaldehyde, according to genetic studies in fission yeast [Noguchi et al, 2017]. …”

“…It has been observed several decades ago that acetaldehyde exposure increases the incidence of mutations, sister chromatid exchanges, micronuclei, and aneuploidy in mammalian cells [Dellarco, 1988]. Replication fork collapse is known to occur from acetaldehyde treatment in fission yeast [Noguchi et al, 2017]. 5-azadC also leads to replication fork collapse in mammalian cells [Orta et al, 2013].…”

Timeless insights into prevention of acetaldehyde genotoxicity?

“…2 Acetaldehyde forms DNA adducts 3 supporting a genotoxic mechanism of carcinogenicity. To identify molecular mechanisms that protect against acetaldehyde genotoxicity, Noguchi et al 4 performed a comprehensive mutational analysis of the role of the DNA repair and DNA damage response pathways, using the fission yeast Schizosaccharomyces pombe as a model organism. The experimental design involved exposing wild-type and mutant strains to increasing concentrations of acetaldehyde, then monitoring cell growth as an end point.…”

“…7 Interestingly, germline mutations in the DVC1-Spartan gene in humans results in premature aging and an increased risk of liver cancer. 7 A summary of the main pathways for protecting against acetaldehyde genotoxicity identified by Noguchi et al 4 is given in Fig. 1.…”