Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast.
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.
a Department of Biochemistry and Molecular Biology , Drexel University College of Medicine , Philadelphia , PA , USA.
Chiaki
C
Noguchi
a Department of Biochemistry and Molecular Biology , Drexel University College of Medicine , Philadelphia , PA , USA.
Grant
G
Grothusen
a Department of Biochemistry and Molecular Biology , Drexel University College of Medicine , Philadelphia , PA , USA.
Vinesh
V
Anandarajan
a Department of Biochemistry and Molecular Biology , Drexel University College of Medicine , Philadelphia , PA , USA.
Marta
M
Martínez-Lage García
a Department of Biochemistry and Molecular Biology , Drexel University College of Medicine , Philadelphia , PA , USA.
Daniel
D
Terlecky
a Department of Biochemistry and Molecular Biology , Drexel University College of Medicine , Philadelphia , PA , USA.
Krysten
K
Corzo
b Department of Bioscience , School of Science and Technology, Kwansei Gakuin University , Sanda , Japan.
Katsunori
K
Tanaka
c Gastroenterology Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine , PA , USA.
Hiroshi
H
Nakagawa
a Department of Biochemistry and Molecular Biology , Drexel University College of Medicine , Philadelphia , PA , USA.
Eishi
E
Noguchi
D000079:Acetaldehyde / Q000633:toxicity*; D000222:Adaptation, Physiological / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004271:DNA, Fungal / Q000096:biosynthesis; D004843:Epistasis, Genetic / Q000187:drug effects; D005199:Fanconi Anemia / Q000235:genetics; D005800:Genes, Fungal; D059765:Homologous Recombination / Q000187:drug effects; D008658:Inactivation, Metabolic / Q000187:drug effects; D008954:Models, Biological; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects / Q000235:genetics*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism
D018736:DNA Adducts; D004271:DNA, Fungal; D029702:Schizosaccharomyces pombe Proteins; D000079:Acetaldehyde
DNA damage; DNA repair; Fanconi anemia; acetaldehyde; alcohol; aldehyde dehydrogenase; crosslink; interstrand crosslink; nucleotide excision repair; replication fork
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