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dc.contributor.authorBass, Adam
dc.contributor.authorChan, Edmond
dc.contributor.authorShibue, Tsukasa
dc.contributor.authorMcFarland, James
dc.contributor.authorGaeta, Benjamin
dc.contributor.authorGhandi, Mahmoud
dc.contributor.authorDumont, Nancy
dc.contributor.authorGonzalez, Alfredo
dc.contributor.authorMcPartlan, Justine
dc.contributor.authorLi, Tianxia
dc.contributor.authorZhang, Yanxi
dc.contributor.authorLiu, Jie Bin
dc.contributor.authorLazaro, Jean-Bernard
dc.contributor.authorGu, Peili
dc.contributor.authorPiett, Cortt
dc.contributor.authorApffel, Annie
dc.contributor.authorAli, Syed Omar
dc.contributor.authorDeasy, Rebecca
dc.contributor.authorKeskula, Paula
dc.contributor.authorNg, Raymond
dc.contributor.authorRoberts, Emma
dc.contributor.authorReznichenko, Elizaveta
dc.contributor.authorLeung, Lisa
dc.contributor.authorAlimova, Maria
dc.contributor.authorSchenone, Monica
dc.contributor.authorIslam, Manirul
dc.contributor.authorMaruvka, Yosef
dc.contributor.authorLiu, Yang
dc.contributor.authorRoper, Jatin
dc.contributor.authorRaghavan, Srivatsan
dc.contributor.authorGiannakis, Marios
dc.contributor.authorTseng, Yuen-Yi
dc.contributor.authorNagel, Zachary
dc.contributor.authorD’Andrea, Alan
dc.contributor.authorRoot, David
dc.contributor.authorBoehm, Jesse
dc.contributor.authorGetz, Gad
dc.contributor.authorChang, Sandy
dc.contributor.authorGolub, Todd
dc.contributor.authorTsherniak, Aviad
dc.contributor.authorVazquez, Francisca
dc.date.accessioned2020-01-10T09:49:28Z
dc.date.issued2018-12-21
dc.identifier.citationChan, Edmond M., Tsukasa Shibue, James M. McFarland, Benjamin Gaeta, Mahmoud Ghandi, Nancy Dumont, Alfredo Gonzalez, Justine S. McPartlan, Tianxia Li, Yanxi Zhang, Jie Bin Liu, Jean-Bernard Lazaro, Peili Gu, Cortt G. Piett, Annie Apffel, Syed O. Ali, Rebecca Deasy, Paula Keskula, Raymond W. S. Ng, Emma A. Roberts, Elizaveta Reznichenko, Lisa Leung, Maria Alimova, Monica Schenone, Mirazul Islam, Yosef E. Maruvka, Yang Liu, Jatin Roper, Srivatsan Raghavan, Marios Giannakis, Yuen-Yi Tseng, Zachary D Nagel, Alan D'Andrea, David E. Root, Jesse S. Boehm, Gad Getz, Sandy Chang, Todd R. Golub, Aviad Tsherniak, Francisca Vazquez, and Adam J. Bass. 2019. WRN Helicase Is a Synthetic Lethal Target in Microsatellite Unstable Cancers. Nature 568, no. 7753: 551-56.en_US
dc.identifier.issn1476-4687en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42137853*
dc.description.abstractSynthetic 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 therapeutics1. 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 proteins2. The success of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitors in homologous recombination-deficient cancers 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 (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 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.en_US
dc.language.isoen_USen_US
dc.publisherCold Spring Harbor Laboratoryen_US
dc.relationNatureen_US
dc.relation.isversionofdoi: 10.1038/s41586-019-1102-xen_US
dc.relation.hasversionhttp://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/pmc/articles/PMC6580861/en_US
dash.licenseLAA
dc.titleWRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancersen_US
dc.typeJournal Articleen_US
dc.description.versionAccepted Manuscripten_US
dc.relation.journalNatureen_US
dash.depositing.authorBass, Adam
dash.waiver2019-02-12
dc.date.available2020-01-10T09:49:28Z
dash.affiliation.otherHarvard Medical Schoolen_US
dash.funder.nameNIHen_US
dash.funder.nameThe Carlos Slim Foundation/Slim Initiative for Genomic Medicineen_US
dash.funder.award2T32CA009172-42A1en_US
dc.identifier.doi10.1038/s41586-019-1102-x
dash.waiver.reasonWe are publishing paper in Nature and must comply with their requests. we will make every effort to make all data and the analysis public.en_US
dash.contributor.affiliatedGonzalez, Alfredo
dash.contributor.affiliatedLi, Tianxia
dash.contributor.affiliatedMcFarland, James
dash.contributor.affiliatedGaeta, Benjamin
dash.contributor.affiliatedZhang, Yanxi
dash.contributor.affiliatedLiu, Yang
dash.contributor.affiliatedReznichenko, Elizaveta
dash.contributor.affiliatedAlimova, Maria
dash.contributor.affiliatedRoberts, Emma
dash.contributor.affiliatedRoper, Jatin
dash.contributor.affiliatedTsherniak, Aviad
dash.contributor.affiliatedChan, Edmond
dash.contributor.affiliatedAli, Syed Omar
dash.contributor.affiliatedNagel, Zachary
dash.contributor.affiliatedBoehm, Jesse
dash.contributor.affiliatedMaruvka, Yosef
dash.contributor.affiliatedLazaro, Jean-Bernard
dash.contributor.affiliatedGolub, Todd
dash.contributor.affiliatedBass, Adam
dash.contributor.affiliatedGetz, Gad
dash.contributor.affiliatedRaghavan, Srivatsan
dash.contributor.affiliatedGiannakis, Marios


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