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Rad5 失调导致复制叉处的过度活跃重组，导致顺铂敏感性和基因组不稳定性。

Rad5 dysregulation drives hyperactive recombination at replication forks resulting in cisplatin sensitivity and genome instability.

机构信息

Department of Biological Sciences, Columbia University, New York, NY 10027, USA.

Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY 10032, USA.

出版信息

Nucleic Acids Res. 2019 Sep 26;47(17):9144-9159. doi: 10.1093/nar/gkz631.

DOI:10.1093/nar/gkz631
PMID:31350889
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6753471/
Abstract

The postreplication repair gene, HLTF, is often amplified and overexpressed in cancer. Here we model HLTF dysregulation through the functionally conserved Saccharomyces cerevisiae ortholog, RAD5. Genetic interaction profiling and landscape enrichment analysis of RAD5 overexpression (RAD5OE) reveals requirements for genes involved in recombination, crossover resolution, and DNA replication. While RAD5OE and rad5Δ both cause cisplatin sensitivity and share many genetic interactions, RAD5OE specifically requires crossover resolving genes and drives recombination in a region of repetitive DNA. Remarkably, RAD5OE induced recombination does not require other post-replication repair pathway members, or the PCNA modification sites involved in regulation of this pathway. Instead, the RAD5OE phenotype depends on a conserved domain necessary for binding 3' DNA ends. Analysis of DNA replication intermediates supports a model in which dysregulated Rad5 causes aberrant template switching at replication forks. The direct effect of Rad5 on replication forks in vivo, increased recombination, and cisplatin sensitivity predicts similar consequences for dysregulated HLTF in cancer.

摘要

复制后修复基因 HLTF 在癌症中经常被扩增和过度表达。在这里，我们通过功能保守的酿酒酵母直系同源物 RAD5 来模拟 HLTF 失调。RAD5 过表达（RAD5OE）的遗传相互作用分析和景观富集分析揭示了涉及重组、交叉解决和 DNA 复制的基因的需求。虽然 RAD5OE 和 rad5Δ 都导致顺铂敏感性，并具有许多遗传相互作用，但 RAD5OE 特异性需要交叉解决基因，并在重复 DNA 区域驱动重组。值得注意的是，RAD5OE 诱导的重组不需要其他复制后修复途径成员，也不需要参与该途径调节的 PCNA 修饰位点。相反，RAD5OE 表型取决于一个保守结构域，该结构域对于结合 3' DNA 末端是必需的。对 DNA 复制中间体的分析支持这样一种模型，即失调的 Rad5 导致复制叉处异常的模板转换。Rad5 在体内对复制叉的直接影响、增加的重组和顺铂敏感性预测了癌症中失调的 HLTF 具有类似的后果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/f36f2d890587/gkz631fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/66f557d11ce3/gkz631fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/bb9eaab05d24/gkz631fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/2dc28a589ab9/gkz631fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/bf4cd88d58e2/gkz631fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/ce488774fbb8/gkz631fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/f36f2d890587/gkz631fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/66f557d11ce3/gkz631fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/bb9eaab05d24/gkz631fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/2dc28a589ab9/gkz631fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/bf4cd88d58e2/gkz631fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/ce488774fbb8/gkz631fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0587/6753471/f36f2d890587/gkz631fig6.jpg

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