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酵母过氧化物酶 Tsa1p 的缺失通过激活 DNA 损伤检查点和提高 dNTP 水平引起基因组不稳定。

Loss of yeast peroxiredoxin Tsa1p induces genome instability through activation of the DNA damage checkpoint and elevation of dNTP levels.

机构信息

Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, People's Republic of China.

出版信息

PLoS Genet. 2009 Oct;5(10):e1000697. doi: 10.1371/journal.pgen.1000697. Epub 2009 Oct 23.

DOI:10.1371/journal.pgen.1000697
PMID:19851444
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2758587/
Abstract

Peroxiredoxins are a family of antioxidant enzymes critically involved in cellular defense and signaling. Particularly, yeast peroxiredoxin Tsa1p is thought to play a role in the maintenance of genome integrity, but the underlying mechanism is not understood. In this study, we took a genetic approach to investigate the cause of genome instability in tsa1Delta cells. Strong genetic interactions of TSA1 with DNA damage checkpoint components DUN1, SML1, and CRT1 were found when mutant cells were analyzed for either sensitivity to DNA damage or rate of spontaneous base substitutions. An elevation in intracellular dNTP production was observed in tsa1Delta cells. This was associated with constitutive activation of the DNA damage checkpoint as indicated by phosphorylation of Rad9/Rad53p, reduced steady-state amount of Sml1p, and induction of RNR and HUG1 genes. In addition, defects in the DNA damage checkpoint did not modulate intracellular level of reactive oxygen species, but suppressed the mutator phenotype of tsa1Delta cells. On the contrary, overexpression of RNR1 exacerbated this phenotype by increasing dNTP levels. Taken together, our findings uncover a new role of TSA1 in preventing the overproduction of dNTPs, which is a root cause of genome instability.

摘要

过氧化物酶是抗氧化酶家族的一个重要成员，在细胞防御和信号转导中起着关键作用。特别是，酵母过氧化物酶 Tsa1p 被认为在维持基因组完整性方面发挥作用，但潜在的机制尚不清楚。在这项研究中，我们采用了一种遗传方法来研究 tsa1Δ 细胞中基因组不稳定性的原因。当分析突变细胞对 DNA 损伤的敏感性或自发碱基替换率时，发现 TSA1 与 DNA 损伤检查点成分 DUN1、SML1 和 CRT1 之间存在强烈的遗传相互作用。在 tsa1Δ 细胞中观察到细胞内 dNTP 产量的升高。这与 DNA 损伤检查点的组成性激活有关，如 Rad9/Rad53p 的磷酸化、Sml1p 的稳定状态减少以及 RNR 和 HUG1 基因的诱导。此外，DNA 损伤检查点的缺陷不会调节细胞内活性氧的水平，但抑制了 tsa1Δ 细胞的突变体表型。相反，RNR1 的过表达通过增加 dNTP 水平加剧了这种表型。总之，我们的发现揭示了 TSA1 在防止 dNTP 过度产生方面的新作用，这是基因组不稳定的根本原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/fa0d4374f157/pgen.1000697.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/aa3ff709d0de/pgen.1000697.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/e7fe73f5c2fa/pgen.1000697.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/5406cb064217/pgen.1000697.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/a00df344d765/pgen.1000697.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/8d7d1b183336/pgen.1000697.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/d0fec2cf078a/pgen.1000697.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/fa0d4374f157/pgen.1000697.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/aa3ff709d0de/pgen.1000697.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/e7fe73f5c2fa/pgen.1000697.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/5406cb064217/pgen.1000697.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/a00df344d765/pgen.1000697.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/8d7d1b183336/pgen.1000697.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/d0fec2cf078a/pgen.1000697.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a19/2758587/fa0d4374f157/pgen.1000697.g007.jpg

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