Journal Article

Repeat expansions confer WRN dependence in microsatellite-unstable cancers

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

2020

Overview

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 1 – 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 nucleotides 5 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/31 / 45 / 45/15 / 45/22 / 45/23 / 45/29 / 45/70 / 45/77 / 631/337/1427 / 631/67/1504 / Apoptosis / Ataxia Telangiectasia Mutated Proteins - metabolism / Biomarkers / Cancer / Cell cycle / Cell Line, Tumor / Chromosomes / Chromosomes, Human - genetics / Chromosomes, Human - metabolism / Chromothripsis / Deoxyribonucleic acid / Dependence / Depletion / Dinucleotide Repeats - genetics / DNA / DNA Breaks, Double-Stranded / DNA Cleavage / DNA damage / DNA helicase / DNA Repeat Expansion - genetics / DNA Replication / DNA-Binding Proteins - metabolism / Endodeoxyribonucleases - metabolism / Endonucleases - metabolism / Gene deletion / Genomes / Genomic Instability / Humanities and Social Sciences / Humans / Insertion / Kinases / Microsatellite instability / multidisciplinary / Mutation / Neoplasms - genetics / Nuclease / Recombinases - metabolism / RecQ protein / Replication forks / Science / Science (multidisciplinary) / Unwinding / Werner Syndrome Helicase - metabolism