Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast.
Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast.
复制标题
裂殖酵母中乙醛反应避免 DNA 损伤的遗传控制。
DOI：
10.1080/15384101.2016.1237326
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Noguchi,Eishi
中科院分区：
文献类型：
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作者：
Noguchi,Chiaki;Grothusen,Grant;Anandarajan,Vinesh;Martínez-LageGarcía,Marta;Terlecky,Daniel;Corzo,Krysten;Tanaka,Katsunori;Nakagawa,Hiroshi;Noguchi,Eishi
乙醛是酒精的主要代谢物，它形成DNA加合物并破坏DNA复制过程，导致基因组不稳定，这是癌症的标志。事实上，慢性酒精消费约占全球所有癌症的3.6%。然而，乙醛暴露后加合物是如何被预防和修复的还不清楚。在这篇报告中，我们使用裂殖酵母作为模式生物，全面了解乙醛对DNA损伤避免的遗传控制。我们证明，Atd 1的功能作为一个主要的乙醛解毒酶，防止Rad 52-DNA修复灶的积累，而Atd 2和Atd 3在乙醛解毒的次要作用。我们发现乙醛在复制叉处引起DNA损伤，并激活细胞周期检查点以协调细胞周期停滞与DNA修复。我们的研究表明，乙酰丙酮介导的DNA加合物包括链间交联和DNA-蛋白质交联。我们还证明，乙醛激活多种DNA修复途径。核苷酸切除修复和同源重组都与范可尼贫血途径上位性相关，在乙醛耐受性中起主要作用，而碱基切除修复和translesion合成也有助于防止乙醛依赖性基因组不稳定性。我们还表明参与WSS 1相关的金属蛋白酶，WSS 1和WSS 2，在乙醛耐受性。这些结果表明，乙醛导致细胞应激，需要细胞协调多个细胞过程，以防止基因组不稳定性。考虑到乙醛是一种人类致癌物，我们的遗传学研究可作为对乙醛依赖性基因组不稳定性和致癌机制的指导性研究。
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 yeastSchizosaccharomyces pombeas 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.