Skip to main content
Journal cover image

WRN helicase is a synthetic lethal target in microsatellite unstable cancers.

Publication ,  Journal Article
Chan, EM; Shibue, T; McFarland, JM; Gaeta, B; Ghandi, M; Dumont, N; Gonzalez, A; McPartlan, JS; Li, T; Zhang, Y; Bin Liu, J; Lazaro, J-B ...
Published in: Nature
April 2019

Synthetic lethality-an interaction between two genetic events through which the co-occurrence of these two genetic events leads to cell death, but each event alone does not-can be exploited for cancer therapeutics1. DNA repair processes represent attractive synthetic lethal targets, because many cancers exhibit an impairment of a DNA repair pathway, which can lead to dependence on specific repair proteins2. The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach3. Hypothesizing that other DNA repair defects would give rise to synthetic lethal relationships, we queried dependencies in cancers with microsatellite instability (MSI), which results from deficient DNA mismatch repair. Here we analysed data from large-scale silencing screens using CRISPR-Cas9-mediated knockout and RNA interference, and found that the RecQ DNA helicase WRN was selectively essential in MSI models in vitro and in vivo, yet dispensable in models of cancers that are microsatellite stable. Depletion of WRN induced double-stranded DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models required the helicase activity of WRN, but not its exonuclease activity. These findings show that WRN is a synthetic lethal vulnerability and promising drug target for MSI cancers.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

April 2019

Volume

568

Issue

7753

Start / End Page

551 / 556

Location

England

Related Subject Headings

  • Werner Syndrome Helicase
  • Tumor Suppressor Protein p53
  • Synthetic Lethal Mutations
  • RNA Interference
  • Neoplasms
  • Models, Genetic
  • Microsatellite Repeats
  • Microsatellite Instability
  • Humans
  • General Science & Technology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chan, E. M., Shibue, T., McFarland, J. M., Gaeta, B., Ghandi, M., Dumont, N., … Bass, A. J. (2019). WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature, 568(7753), 551–556. https://doi.org/10.1038/s41586-019-1102-x
Chan, Edmond M., Tsukasa Shibue, James M. McFarland, Benjamin Gaeta, Mahmoud Ghandi, Nancy Dumont, Alfredo Gonzalez, et al. “WRN helicase is a synthetic lethal target in microsatellite unstable cancers.Nature 568, no. 7753 (April 2019): 551–56. https://doi.org/10.1038/s41586-019-1102-x.
Chan EM, Shibue T, McFarland JM, Gaeta B, Ghandi M, Dumont N, et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature. 2019 Apr;568(7753):551–6.
Chan, Edmond M., et al. “WRN helicase is a synthetic lethal target in microsatellite unstable cancers.Nature, vol. 568, no. 7753, Apr. 2019, pp. 551–56. Pubmed, doi:10.1038/s41586-019-1102-x.
Chan EM, Shibue T, McFarland JM, Gaeta B, Ghandi M, Dumont N, Gonzalez A, McPartlan JS, Li T, Zhang Y, Bin Liu J, Lazaro J-B, Gu P, Piett CG, Apffel A, Ali SO, Deasy R, Keskula P, Ng RWS, Roberts EA, Reznichenko E, Leung L, Alimova M, Schenone M, Islam M, Maruvka YE, Liu Y, Roper J, Raghavan S, Giannakis M, Tseng Y-Y, Nagel ZD, D’Andrea A, Root DE, Boehm JS, Getz G, Chang S, Golub TR, Tsherniak A, Vazquez F, Bass AJ. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature. 2019 Apr;568(7753):551–556.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

April 2019

Volume

568

Issue

7753

Start / End Page

551 / 556

Location

England

Related Subject Headings

  • Werner Syndrome Helicase
  • Tumor Suppressor Protein p53
  • Synthetic Lethal Mutations
  • RNA Interference
  • Neoplasms
  • Models, Genetic
  • Microsatellite Repeats
  • Microsatellite Instability
  • Humans
  • General Science & Technology