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促进卵巢癌细胞中错误的 DNA 合成。

Error-promoting DNA synthesis in ovarian cancer cells.

机构信息

Indiana University School of Medicine, Department of Medicine, Division of Clinical Pharmacology, USA.

出版信息

Gynecol Oncol. 2013 Oct;131(1):198-206. doi: 10.1016/j.ygyno.2013.06.022. Epub 2013 Jul 12.

DOI:10.1016/j.ygyno.2013.06.022
PMID:23851291
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3796037/
Abstract

OBJECTIVE

The objective of this study is to determine whether an altered DNA replication process is responsible for some of genetic damage observed in ovarian cancer.

METHODS

The replication fidelity of the DNA synthetic process was evaluated in both malignant and non-malignant human ovarian cells. The types of replication errors produced were identified. In addition, kinetic analyses of the efficiency of ovarian cancer DNA polymerases for misincorporating nucleotides were performed.

RESULTS

We report for the first time that ovarian cancer cells harbor an error promoting DNA replication apparatus which contributes to the decrease in DNA synthetic fidelity exhibited by these cells. Our study also shows that the decrease in DNA replication fidelity was not a result of an increased DNA replication activity. In addition, it was observed that the higher rate of DNA replication errors does not result in significant differences in the type of DNA replication-errors made during the DNA replication process; just the relative abundance. A detailed kinetic analysis of the efficiency of misincorporating nucleotides demonstrated that the DNA polymerases within the ovarian cancer cells exhibited a significant propensity for creating purine-pyrimidine nucleotide mismatches relative to non-malignant ovarian cells, while being only slightly more efficient at incorrectly pairing a purine nucleotide with a purine nucleotide.

CONCLUSIONS

All together, these data suggest that the systematic analysis of the DNA replication process in ovarian cancer could uncover information on some of the molecular mechanisms that drive the accumulation of genetic damage, and probably contribute to the pathogenesis of the disease.

摘要

目的

本研究旨在确定 DNA 复制过程的改变是否是卵巢癌中观察到的某些遗传损伤的原因。

方法

评估了恶性和非恶性人卵巢细胞中 DNA 合成过程的复制保真度。确定了产生的复制错误类型。此外，还对卵巢癌细胞 DNA 聚合酶错误掺入核苷酸的效率进行了动力学分析。

结果

我们首次报道卵巢癌细胞具有促进错误的 DNA 复制装置，这有助于降低这些细胞的 DNA 合成保真度。我们的研究还表明，DNA 复制保真度的降低不是由于 DNA 复制活性增加所致。此外，观察到较高的 DNA 复制错误率并不会导致 DNA 复制过程中发生的 DNA 复制错误类型有显着差异；只是相对丰度。对核苷酸错误掺入效率的详细动力学分析表明，与非恶性卵巢细胞相比，卵巢癌细胞中的 DNA 聚合酶在创建嘌呤-嘧啶核苷酸错配方面具有显着的倾向，而与嘌呤核苷酸与嘌呤核苷酸配对错误的效率仅略高。

结论

总而言之，这些数据表明，对卵巢癌中 DNA 复制过程的系统分析可以揭示一些驱动遗传损伤积累的分子机制的信息，并可能有助于该疾病的发病机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/a6053f76d7a7/nihms502577f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/25f4ec2c34bd/nihms502577f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/130ec1d97d41/nihms502577f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/fc00cee10dc5/nihms502577f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/a6053f76d7a7/nihms502577f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/25f4ec2c34bd/nihms502577f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/130ec1d97d41/nihms502577f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/fc00cee10dc5/nihms502577f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15ea/3796037/a6053f76d7a7/nihms502577f4.jpg

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本文引用的文献

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Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression.多倍体细胞重新布线 DNA 损伤反应网络，以克服复制应激诱导的肿瘤进展障碍。
Nat Commun. 2012 May 8;3:815. doi: 10.1038/ncomms1825.
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Hallmarks of cancer: the next generation.癌症的特征：下一代。
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Detection of the Replication Error Phenotype in Ovarian Cancer-PCR Analysis of Microsatellite Instability.
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More forks on the road to replication stress recovery.复制压力恢复之路上的更多分岔口。
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Mutational heterogeneity in human cancers: origin and consequences.人类癌症中的突变异质性：起源与后果。
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