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微卫星不稳定性癌细胞中重复扩增赋予WRN依赖性
2020-10-02 23:31

美国国立卫生研究院国家癌症研究所Andr Nussenzweig研究组在研究中取得进展。他们的最新研究发现在微卫星不稳定性(MSI)癌症细胞中重复扩增赋予WRN依赖性。相关论文在线发表在2020年9月30日出版的《自然》杂志上。

研究人员发现TA-二核苷酸重复序列在MSI细胞中高度不稳定,并发生大规模扩增,这与先前报道的一些核苷酸的插入或缺失突变不同。扩增的TA重复序列形成非B DNA二级结构,使复制叉停滞,激活ATR检查点激酶,并需要WRN解旋酶解链。在没有WRN的情况下,扩增的TA-二核苷酸重复序列易受MUS81核酸酶的切割,导致大量染色体断裂。这些发现确定了独特的生物标记物,该标记物是WRN合成致死依赖性的基础,并有利于MSI相关癌症靶向WRN治疗剂的研发。

研究人员表示,RecQ DNA解旋酶WRN是具有微卫星不稳定性的癌细胞合成致死靶标,MSI是一种遗传的超变异形式,由错配修复损伤引起。WRN耗竭会在MSI细胞中诱导广泛的DNA双链断裂,从而导致细胞周期停滞和/或凋亡。但是,WRN保护MSI相关癌症免遭双链断裂的机制仍不清楚。

附:英文原文

Title: Repeat expansions confer WRN dependence in microsatellite-unstable cancers

Author: Niek van Wietmarschen, Sriram Sridharan, William J. Nathan, Anthony Tubbs, Edmond M. Chan, Elsa Callen, Wei Wu, Frida Belinky, Veenu Tripathi, Nancy Wong, Kyla Foster, Javad Noorbakhsh, Kiran Garimella, Abimael Cruz-Migoni, Joshua A. Sommers, Yongqing Huang, Ashir A. Borah, Jonathan T. Smith, Jeremie Kalfon, Nikolas Kesten, Kasper Fugger, Robert L. Walker, Egor Dolzhenko, Michael A. Eberle, Bruce E. Hayward, Karen Usdin, Catherine H. Freudenreich, Robert M. Brosh, Stephen C. West, Peter J. McHugh, Paul S. Meltzer, Adam J. Bass, Andr Nussenzweig

Issue&Volume: 2020-09-30

Abstract: The RecQ DNA helicase WRN is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair1–4. Depletion of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI-associated cancers from double-strand breaks remains unclear. Here we show that TA-dinucleotide repeats are highly unstable in MSI cells and undergo large-scale expansions, distinct from previously described insertion or deletion mutations of a few nucleotides5. Expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and require unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 nuclease, leading to massive chromosome shattering. These findings identify a distinct biomarker that underlies the synthetic lethal dependence on WRN, and support the development of therapeutic agents that target WRN for MSI-associated cancers. In cells with microsatellite instability, expanded TA-dinucleotide repeats form cruciform structures that stall replication forks and cause chromosome shattering in the absence of the WRN helicase.

DOI: 10.1038/s41586-020-2769-8

Source: https://www.nature.com/articles/s41586-020-2769-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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