Journal article
Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast
Cell cycle (Georgetown, Tex.), v 16(1)
02 Jan 2017
PMID: 27687866
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast
- Creators
- Chiaki Noguchi - Department of Biochemistry and Molecular Biology, Drexel University College of MedicineGrant Grothusen - Department of Biochemistry and Molecular Biology, Drexel University College of MedicineVinesh Anandarajan - Department of Biochemistry and Molecular Biology, Drexel University College of MedicineMarta Martínez-Lage García - Department of Biochemistry and Molecular Biology, Drexel University College of MedicineDaniel Terlecky - Department of Biochemistry and Molecular Biology, Drexel University College of MedicineKrysten Corzo - Department of Biochemistry and Molecular Biology, Drexel University College of MedicineKatsunori Tanaka - Department of Bioscience, School of Science and Technology, Kwansei Gakuin UniversityHiroshi Nakagawa - Gastroenterology Division, Department of Medicine, University of Pennsylvania Perelman School of MedicineEishi Noguchi - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine
- Publication Details
- Cell cycle (Georgetown, Tex.), v 16(1)
- Publisher
- Taylor & Francis
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000392737300014
- Scopus ID
- 2-s2.0-84996848892
- Other Identifier
- 991014878155404721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology