WRN helicase is a synthetic lethal target in microsatellite unstable cancers

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 c...

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Published inNature (London) Vol. 568; no. 7753; pp. 551 - 556
Main Authors Chan, Edmond M., Shibue, Tsukasa, McFarland, James M., Gaeta, Benjamin, Ghandi, Mahmoud, Dumont, Nancy, Gonzalez, Alfredo, McPartlan, Justine S., Li, Tianxia, Zhang, Yanxi, Bin Liu, Jie, Lazaro, Jean-Bernard, Gu, Peili, Piett, Cortt G., Apffel, Annie, Ali, Syed O., Deasy, Rebecca, Keskula, Paula, Ng, Raymond W. S., Roberts, Emma A., Reznichenko, Elizaveta, Leung, Lisa, Alimova, Maria, 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, Vazquez, Francisca, Bass, Adam J.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.04.2019
Nature Publishing Group
Subjects
13
13/2
13/89
14
14/1
14/19
14/35
38/39
38/91
42/41
631/67/1059/602
631/67/68
631/67/69
96/1
Adenosine diphosphate
Analysis
Apoptosis
Apoptosis - genetics
Biomarkers
Cancer
Cell cycle
Cell Cycle Checkpoints - genetics
Cell death
Cell Line, Tumor
CRISPR
CRISPR-Cas Systems - genetics
CRISPR-Cas technology
Datasets
Deoxyribonucleic acid
Dependence
Depletion
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA helicase
DNA repair
Exonuclease
Gene expression
Genetic research
Genomes
Helicases
Homologous recombination
Homology
Humanities and Social Sciences
Humans
Instability
Kinases
Lethality
Letter
Microsatellite Instability
Microsatellite Repeats - genetics
Mismatch repair
Models, Genetic
multidisciplinary
Mutation
Neoplasms - genetics
Neoplasms - pathology
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
RecQ protein
Repair
Ribose
RNA Interference
RNA-mediated interference
Science
Science (multidisciplinary)
Stability
Stability analysis
Synthetic biology
Synthetic Lethal Mutations - genetics
Tumor Suppressor Protein p53 - metabolism
Werner syndrome
Werner Syndrome Helicase - deficiency
Werner Syndrome Helicase - genetics
United States > US
Online AccessGet full text

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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. Depletion of the DNA helicase WRN induced double-stranded DNA breaks, and promoted apoptosis and cell cycle arrest selectively in cancers with microsatellite instability, indicating that WRN is a promising drug target for the treatment of these cancers.
AbstractList 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. 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. The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach. 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.
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.sup.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.sup.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.sup.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.
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 . 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 . The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach . 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.
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.sup.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.sup.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.sup.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. Depletion of the DNA helicase WRN induced double-stranded DNA breaks, and promoted apoptosis and cell cycle arrest selectively in cancers with microsatellite instability, indicating that WRN is a promising drug target for the treatment of these cancers.
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. Depletion of the DNA helicase WRN induced double-stranded DNA breaks, and promoted apoptosis and cell cycle arrest selectively in cancers with microsatellite instability, indicating that WRN is a promising drug target for the treatment of these cancers.
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.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.
Synthetic lethality, an interaction whereby the co-occurrence of two genetic events leads to cell death but one event alone does not, can be exploited for cancer therapeutics 1 . DNA repair processes represent attractive synthetic lethal targets since many cancers exhibit an impaired 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 homologous recombination-deficient cancers 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 (dMMR). Here we analyzed data from large-scale CRISPR/Cas9 knockout and RNA interference (RNAi) silencing screens and found that the RecQ DNA helicase WRN was selectively essential in MSI models in vitro and in vivo , yet dispensable in microsatellite stable (MSS) models. WRN depletion induced double-strand DNA breaks (DSB) and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models required the helicase activity, but not the exonuclease activity of WRN. These findings expose WRN as a synthetic lethal vulnerability and promising drug target for MSI cancers.
Audience Academic
Author Tseng, Yuen-Yi
Deasy, Rebecca
Ng, Raymond W. S.
Zhang, Yanxi
Islam, Mirazul
Root, David E.
Shibue, Tsukasa
Gu, Peili
Dumont, Nancy
Golub, Todd R.
Nagel, Zachary D.
Piett, Cortt G.
Raghavan, Srivatsan
Leung, Lisa
Ali, Syed O.
Reznichenko, Elizaveta
Lazaro, Jean-Bernard
Vazquez, Francisca
Chan, Edmond M.
Alimova, Maria
Schenone, Monica
McFarland, James M.
Ghandi, Mahmoud
Apffel, Annie
D’Andrea, Alan
Chang, Sandy
Liu, Yang
Roper, Jatin
Giannakis, Marios
Li, Tianxia
McPartlan, Justine S.
Boehm, Jesse S.
Gonzalez, Alfredo
Bin Liu, Jie
Maruvka, Yosef E.
Tsherniak, Aviad
Gaeta, Benjamin
Getz, Gad
Keskula, Paula
Roberts, Emma A.
Bass, Adam J.
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  organization: Broad Institute of Harvard and MIT, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30971823$$D View this record in MEDLINE/PubMed
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These authors contributed equally: Edmond M. Chan and Tsukasa Shibue
E.M.C., T.S., F.V., and A.J.B. initiated the project, designed, and supervised the research plan. J.M.M., M.Gh., Y.L., and Y.E.M. performed computational analysis of the CCLE and cancer dependency datasets under the supervision of D.E.R, J.S.B., G.G., T.R.G., A.T., F.V., and A.J.B.. E.M.C., T.S., B.G., and J.S.M. performed the viability experiments to validate the cancer dependency dataset findings with help from M.S., A.A., S.A.O., and L.L.. The rescue experiments with WRN overexpression were performed by E.M.C. and B.G.. The HCT116 viability experiments were performed by T.S. and B.G.. N.D., A.G., T.L., and Y.Z. performed in vivo experiments. The patient derived organoids were established by J.S.B., Y.Y.T., M.Gi., R.D., and P.K.. Organoid experiments were conducted by E.M.C. and T.S. with help from S.R., R.W.S.N, and J.R.. RNA extraction for mRNA-seq was performed by T.S. and analyzed by J.M.M. and M.I.. J.S.M. and T.S. performed and analyzed the cell cycle and apoptosis assays. Immunoblots were performed by T.S., E.M.C., B.G., and J.S.M. Immunofluorescence were performed by T.S., E.M.C., J.B.L., J.L., E.A.R, and E.R. and analyzed by T.S., E.M.C., J.B.L., J.L., M.A., and A.D.A.. S.C. and P.G. performed the telomere PNA-FISH experiment. Z.N. and C.G.P. performed the fluorescence-based flow-cytometric host cell reactivation assay. E.M.C., T.S., J.M.M., F.V., and A.J.B. wrote the manuscript. All the authors edited and approved the manuscript.
Author Contributions
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Snippet 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...
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...
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...
Synthetic lethality, an interaction whereby the co-occurrence of two genetic events leads to cell death but one event alone does not, can be exploited for...
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Publisher
StartPage 551
SubjectTerms 13
13/2
13/89
14
14/1
14/19
14/35
38/39
38/91
42/41
631/67/1059/602
631/67/68
631/67/69
96/1
Adenosine diphosphate
Analysis
Apoptosis
Apoptosis - genetics
Biomarkers
Cancer
Cell cycle
Cell Cycle Checkpoints - genetics
Cell death
Cell Line, Tumor
CRISPR
CRISPR-Cas Systems - genetics
CRISPR-Cas technology
Datasets
Deoxyribonucleic acid
Dependence
Depletion
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA helicase
DNA repair
Exonuclease
Gene expression
Genetic research
Genomes
Helicases
Homologous recombination
Homology
Humanities and Social Sciences
Humans
Instability
Kinases
Lethality
Letter
Microsatellite Instability
Microsatellite Repeats - genetics
Mismatch repair
Models, Genetic
multidisciplinary
Mutation
Neoplasms - genetics
Neoplasms - pathology
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
RecQ protein
Repair
Ribose
RNA Interference
RNA-mediated interference
Science
Science (multidisciplinary)
Stability
Stability analysis
Synthetic biology
Synthetic Lethal Mutations - genetics
Tumor Suppressor Protein p53 - metabolism
Werner syndrome
Werner Syndrome Helicase - deficiency
Werner Syndrome Helicase - genetics
Title WRN helicase is a synthetic lethal target in microsatellite unstable cancers
URI https://link.springer.com/article/10.1038/s41586-019-1102-x
https://www.ncbi.nlm.nih.gov/pubmed/30971823
https://www.proquest.com/docview/2254474426
https://www.proquest.com/docview/2207940543
https://pubmed.ncbi.nlm.nih.gov/PMC6580861
Volume 568
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