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This work shows that PACT, a dsRNA-binding protein highly expressed in many TNBC lines, suppresses PKR activation via dsRNA binding and dimerization. Depleting PACT triggers PKR-dependent robust activation of integrated stress response genes and NF-κB targets, while combined PACT and ADAR1 depletion reinforces PKR-driven cell death, supporting PACT as a therapeutic target.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/pact-suppresses-pkr-activation-through-dsrna-binding-and-dimerization-and-is-a-therapeutic-target-for-triple-negative-breast-cancer/372755/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/pact-suppresses-pkr-activation-through-dsrna-binding-and-dimerization-and-is-a-therapeutic-target-for-triple-negative-breast-cancer/372755.png","ImageObject",300,407,{"name":92,"@type":93},"Well Done","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-01","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is PACT considered important for TNBC therapy in this study?","Question",{"text":112,"@type":113},"PACT is required for suppressing PKR activation in many TNBC cell lines, and targeting PACT can induce PKR-dependent cell death.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Does increasing PACT alone activate PKR in TNBC cell lines?",{"text":117,"@type":113},"Overexpression of PACT had no effect on PKR activation across multiple TNBC cell lines.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanisms does PACT use to suppress PKR activation?",{"text":121,"@type":113},"PACT dimerization and dsRNA binding are both required for suppressing PKR activation, as shown by rescue experiments.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},372755,1790792565,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":31},5909892210082,"https://ap-avatar.wpscdn.com/avatar/56001069da27c9f41e8?x-image-process=image/resize,m_fixed,w_180,h_180&k=1789614185077863061","PACT suppresses PKR activation through dsRNA binding and dimerization, and is a therapeutic target for triple-negative breast cancer  \nADDISON A. YOUNG,1 ISABELLEG. JUHLER,1 JACKSON R. PIERCE,1 HOLLY E. BOHLIN,1 HALEYA. HARPER,2 DAVID S. ONISHILE,1 RENEE N. CHUA,1 MADISON E. LIU,1 ESTELLE N. GARDNER,1 BENNETT D. ELZEY,2,3 and KYLE A. COTTRELL1,2  \n1Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA  \n2Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA 3Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47907, USA  \nABSTRACT  \nTriple-negative breast cancer (TNBC), the deadliest breast cancer subtype, lacks broadly applicable targeted therapies. Induction of “viral mimicry” by activation of viral double-stranded RNA (dsRNA) sensors has potential therapeutic applications for TNBC and other cancers. Suppressors of dsRNA sensing prevent sensing of endogenous dsRNAs and resulting autoimmunity. Depletion of the suppressor of dsRNA sensing ADAR1 causes activation of dsRNA sensors and cell death in many cancer cell lines. These ADAR1-dependent cells are generally also dependent on the dsRNA-binding protein PACT, which is highly expressed and essential in many TNBC cell lines. While PACT is known as an activator of the dsRNA sensor PKR, overexpression of PACT had no effect on activation of PKR in multiple TNBC cell lines. Conversely, depletion of PACT in PACT-dependent cell lines caused robust activation of PKR and cell death, in addition to induction of integrated stress response genes and NF-κB targets. These phenotypes were entirely dependent on PKR. Rescue experiments revealed that PACT dimerization and dsRNA binding are required to suppress PKR activation. While depletion of PACT alone in ADAR1/PACT-independent cell lines had no effect on PKR activation, combined depletion of both PACT andADAR1 in those cell lines caused robust PKR activation and cell death, supporting a partially redundant role forADAR1 and PACT in suppression of dsRNA sensing. Taken together, these findings support a vital role for PACT in suppressing PKR activation and highlight the therapeutic potential of targeting PACT to treat TNBC.  \nKeywords: dsRNA; cancer; PACT; ADAR1; RBP; PKR  \nINTRODUCTION  \nTriple-negative breast cancer (TNBC) is the deadliest form of breast cancer, with high rates of recurrence and metastasis (Curigliano and Goldhirsch 2011; Bianchiniet al. 2016) . A major factor driving the poor patient outcomes is the lack of broadly applicable targeted therapies for TNBC (Curigliano and Goldhirsch 2011; Bianchini et al. 2016; Waks and Winer 2019) . Immunotherapies, such as immune checkpoint blockade (ICB), have shown some efficacy in TNBC, but many tumors are resistant (Morad et al. 2021) . Often, tumors with increased inflammation, known as immunologically“hot”(immune inflamed), are more sensitive to ICB, rela-  \ntive to “cold” (immune excluded) tumors (Chen and Mellman 2017) . Several recent studies have shown that increasing inflammation within tumors can overcome resistance to ICB (Ishizuka et al. 2019; Jiang et al. 2019; Guirguis et al. 2023; Huang et al. 2024; Young et al. 2024) . A great example of this approach is targeting the RNA editor ADAR1 to overcome resistance to ICB in mouse tumor models (Ishizuka et al. 2019) .  \nAdenosine deaminase acting on RNA (ADAR, which encodes ADAR1) has been identified as an essential gene in multiple cancer cell lines—including those derived from breast, lung, and ovarian cancer (Gannon et al. 2018; Liu et al. 2019b; Kung et al. 2021) . ADAR1 deaminates adenosine to inosine in double-stranded RNAs (dsRNA) in a  \nCorresponding author: [kacottre@purdue.edu](kacottre@purdue.edu)  \nHandling editor: Maria Carmo-Fonseca  \nArticle is online at [http://www.rnajournal.org/cgi/doi/10.1261/rna](http://www.rnajournal.org/cgi/doi/10.1261/rna)[.080637.125. Freely available online through the](.080637.125. Freely avai","cbCainJpSRXri4Cz","https://ap.wps.com/l/cbCainJpSRXri4Cz","pdf",5233622,"English","# Abstract\n# Keywords\n# Introduction","[{\"question\":\"Why is PACT considered important for TNBC therapy in this study?\",\"answer\":\"PACT is required for suppressing PKR activation in many TNBC cell lines, and targeting PACT can induce PKR-dependent cell death.\"},{\"question\":\"Does increasing PACT alone activate PKR in TNBC cell lines?\",\"answer\":\"Overexpression of PACT had no effect on PKR activation across multiple TNBC cell lines.\"},{\"question\":\"What mechanisms does PACT use to suppress PKR activation?\",\"answer\":\"PACT dimerization and dsRNA binding are both required for suppressing PKR activation, as shown by rescue experiments.\"}]","PACT suppresses PKR activation through dsRNA binding and dimerization, and is a therapeutic target for triple-negative breast cancer | PDF",1790195295]