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具有环状染色体的裂殖酵母菌株在应对抗癌药物5-氟脱氧尿苷时，需要9-1-1检查点复合物来维持生存能力。

Fission yeast strains with circular chromosomes require the 9-1-1 checkpoint complex for the viability in response to the anti-cancer drug 5-fluorodeoxyuridine.

作者信息

Shamim Hossain Mohammad, Minami Yukako, Tanaka Daiki, Ukimori Shinobu, Murray Johanne M, Ueno Masaru

机构信息

Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Japan.

Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, United Kingdom.

出版信息

PLoS One. 2017 Nov 9;12(11):e0187775. doi: 10.1371/journal.pone.0187775. eCollection 2017.

DOI:10.1371/journal.pone.0187775
PMID:29121084
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5679574/
Abstract

Thymidine kinase converts 5-fluorodeoxyuridine to 5-fluorodeoxyuridine monophosphate, which causes disruption of deoxynucleotide triphosphate ratios. The fission yeast Schizosaccharomyces pombe does not express endogenous thymidine kinase but 5-fluorodeoxyuridine inhibits growth when exogenous thymidine kinase is expressed. Unexpectedly, we found that 5-fluorodeoxyuridine causes S phase arrest even without thymidine kinase expression. DNA damage checkpoint proteins such as the 9-1-1 complex were required for viability in the presence of 5-fluorodeoxyuridine. We also found that strains with circular chromosomes, due to loss of pot1+, which have higher levels of replication stress, were more sensitive to loss of the 9-1-1 complex in the presence of 5-fluorodeoxyuridine. Thus, our results suggest that strains carrying circular chromosomes exhibit a greater dependence on DNA damage checkpoints to ensure viability in the presence of 5-fluorodeoxyuridine compared to stains that have linear chromosomes.

摘要

胸苷激酶将5-氟脱氧尿苷转化为5-氟脱氧尿苷一磷酸，这会导致脱氧核苷酸三磷酸比例失衡。裂殖酵母粟酒裂殖酵母不表达内源性胸苷激酶，但当表达外源性胸苷激酶时，5-氟脱氧尿苷会抑制其生长。出乎意料的是，我们发现即使没有胸苷激酶表达，5-氟脱氧尿苷也会导致S期停滞。在存在5-氟脱氧尿苷的情况下，DNA损伤检查点蛋白如9-1-1复合物对于细胞存活是必需的。我们还发现，由于pot1+缺失而具有环状染色体的菌株，其复制应激水平较高，在存在5-氟脱氧尿苷的情况下对9-1-1复合物的缺失更敏感。因此，我们的结果表明，与具有线性染色体的菌株相比，携带环状染色体的菌株在存在5-氟脱氧尿苷的情况下对DNA损伤检查点的依赖性更大，以确保细胞存活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/6b6f958aa7f1/pone.0187775.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/f170ecdbcfe2/pone.0187775.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/ad7cc6fec448/pone.0187775.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/fd38e1f034a6/pone.0187775.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/8ae9ec103a73/pone.0187775.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/6b6f958aa7f1/pone.0187775.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/f170ecdbcfe2/pone.0187775.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/ad7cc6fec448/pone.0187775.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/fd38e1f034a6/pone.0187775.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/8ae9ec103a73/pone.0187775.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f9/5679574/6b6f958aa7f1/pone.0187775.g005.jpg

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Int J Oncol. 2015;46(6):2327-34. doi: 10.3892/ijo.2015.2974. Epub 2015 Apr 20.
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Standing the test of time: targeting thymidylate biosynthesis in cancer therapy.经得起时间考验的策略：以胸苷酸合成为靶点的癌症治疗。
Nat Rev Clin Oncol. 2014 May;11(5):282-98. doi: 10.1038/nrclinonc.2014.51. Epub 2014 Apr 15.
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Fission yeast RecQ helicase Rqh1 is required for the maintenance of circular chromosomes.
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Mol Cell Biol. 2013 Mar;33(6):1175-87. doi: 10.1128/MCB.01713-12. Epub 2013 Jan 7.
4
Genome-wide screening with hydroxyurea reveals a link between nonessential ribosomal proteins and reactive oxygen species production.羟基脲的全基因组筛选揭示了非必需核糖体蛋白与活性氧产生之间的联系。
J Bacteriol. 2013 Mar;195(6):1226-35. doi: 10.1128/JB.02145-12. Epub 2013 Jan 4.
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