Diagenode

Repeat expansions confer WRN dependence in microsatellite-unstablecancers.


van Wietmarschen, Niek and Sridharan, Sriram and Nathan, William J andTubbs, Anthony and Chan, Edmond M and Callen, Elsa and Wu, Wei and Belinky,Frida and Tripathi, Veenu and Wong, Nancy and Foster, Kyla and Noorbakhsh,Javad and Garimella, Kiran and Cr

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 repair. 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 nucleotides. 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.

Tags
Megaruptor

Share this article

Published
October, 2020

Source

Products used in this publication

  • Megaruptor 3
    B06010003
    Megaruptor® 3

イベント

  • AACR 2024
    San Diego, California, USA
    Apr 5-Apr 10, 2024
 すべてのイベントを見る

ニュース

 すべてのニュースを見る


The European Regional Development Fund and Wallonia are investing in your future.

Extension of industrial buildings and new laboratories.


       Site map   |   Contact us   |   Conditions of sales   |   Conditions of purchase   |   Privacy policy   |   Diagenode Diagnostics