WRN helicase is a synthetic lethal target in microsatellite unstable cancers
Open accessPublished version of a preprint
Abstract
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 therapeutics 1. 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 proteins 2. The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach 3. 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.
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MSI that often leads to cancer simultaneously makes the inhibition of WRN lethal to tumor cells.
“the MSI that often leads to cancer simultaneously makes the inhibition of Werner syndrome ATP-dependent helicase (WRN) lethal to the tumor cells62,63”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [63]
WRN has been identified as a synthetically lethal target of MSI-H cancers.
“recent reports have identified WRN as a synthetically lethal target of MSI-H cancers”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Chan et al., 2019
WRN has been proposed to be a CDK12 target.
“WRN has been proposed to be a CDK12 target (Chan et al., 2019;Dubbury et al., 2018).”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Chan et al., 2019
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- Authors
- Chan, E. M., Shibue, T., McFarland, J. M., Gaeta, B., Ghandi, M., Dumont, N., Gonzalez, A., McPartlan, J. S., Li, T., Zhang, Y., Bin Liu, J., Lazaro, J.-B., Gu, P., Piett, C. G., Apffel, A., Ali, S. O., Deasy, R., Keskula, P., Ng, R. W. S., Roberts, E. A., Reznichenko, E., Leung, L., Alimova, M., Schenone, M., Islam, M., Maruvka, Y. E., Liu, Y., Roper, J., Raghavan, S., Giannakis, M., Tseng, Y.-Y., Nagel, Z. D., D’Andrea, A., Root, D. E., Boehm, J. S., Getz, G., Chang, S., Golub, T. R., Tsherniak, A., Vazquez, F., & Bass, A. J.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Yale University (US)
- Duke University (US)
- Corresponding author
- Bass, Adam J.
- ORCID
- Chan, Edmond M.
- Shibue, Tsukasa
- McFarland, James M.
- Gaeta, Benjamin
- Ghandi, Mahmoud
- Dumont, Nancy
- Gonzalez, Alfredo
- Li, Tianxia
- Lazaro, Jean-Bernard
- Piett, Cortt G.
- Apffel, Annie
- Ali, Syed O.
- Deasy, Rebecca
- Keskula, Paula
- Ng, Raymond W. S.
- Roberts, Emma A.
- Reznichenko, Elizaveta
- Leung, Lisa
- Schenone, Monica
- Islam, Mirazul
- Maruvka, Yosef E.
- Liu, Yang
- Roper, Jatin
- Raghavan, Srivatsan
- Giannakis, Marios
- Tseng, Yuen-Yi
- Nagel, Zachary D.
- D’Andrea, Alan
- Root, David E.
- Boehm, Jesse S.
- Getz, Gad
- Chang, Sandy
- Golub, Todd R.
- Tsherniak, Aviad
- Bass, Adam J.
- Venue
- Nature
- Published
- 2019-04-10
- Volume
- 568
- Issue
- 7753
- Pages
- 551-556
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6580861
- OpenAlex
- W2905437169
- Cited by
- 458
- References
- 48
- Citations by year
- 2026: 67 · 2025: 80 · 2024: 75 · 2023: 32 · 2022: 60 · 2021: 73 · 2020: 47 · 2019: 22 · 2012: 1
- FWCI
- 38.46
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Broad Institute
- National Institutes of Health
- National Cancer Institute (K08CA198002, T32CA009172, P30CA014236)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034854)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- WRN helicase, synthetic lethality, microsatellite instability, mismatch repair deficiency, RecQ helicase, DNA repair deficiency, cancer drug targets, DNA double-strand breaks, apoptosis, cell cycle arrest, exonuclease activity, CRISPR-Cas9 knockout screen, RNAi screen
- MeSH terms
- Werner Syndrome Helicase, Synthetic Lethal Mutations, Humans, Models, Genetic, Neoplasms, Tumor Suppressor Protein p53, Apoptosis, Microsatellite Repeats, RNA Interference, Cell Line, Tumor, Microsatellite Instability, DNA Breaks, Double-Stranded, Cell Cycle Checkpoints, CRISPR-Cas Systems
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