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This study identifies RNA degradation and downstream ribonucleotide catabolism as a novel MYC-driven mechanism of cancer cell death. Using genetics and metabolomics, the work shows MYC enhances cytoplasmic exosome-mediated RNA decay, causing cytotoxic RNA catabolites and reactive oxygen species accumulation.",{"@graph":69,"@context":123},[70,84,106],{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/myc-induces-oncogenic-stress-through-rna-decay-and-ribonucleotide-catabolism-in-breast-cancer/331253/",{"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/myc-induces-oncogenic-stress-through-rna-decay-and-ribonucleotide-catabolism-in-breast-cancer/331253.png","ImageObject",300,407,{"name":92,"@type":93},"Theodore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-02","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"How does MYC contribute to oncogenic stress in breast cancer cells?","Question",{"text":113,"@type":114},"MYC increases cytoplasmic exosome-mediated RNA decay, leading to accumulation of cytotoxic RNA catabolites and reactive oxygen species. This RNA degradation and ribonucleotide catabolism trigger oncogenic cell death and stress.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What role do exosome mutations play in MYC-induced cell death?",{"text":118,"@type":114},"Tumor-derived exosome mutations can abrogate MYC-induced cell death, indicating that excess RNA decay is a toxic mechanism relevant to human cancers.",{"name":120,"@type":111,"acceptedAnswer":121},"Why do purine salvage pathways matter for MYC-driven progression?",{"text":122,"@type":114},"Purine salvage compensates for MYC-induced ribonucleotide catabolism and mitigates its effects. Inhibitors of purine salvage impair MYC-positive tumor progression, suggesting a therapeutic vulnerability.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},331253,1790468196,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},7971461740886,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","ReseaRch aRticle  \nMYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in  \nBreast Cancer   \nJitendra K. Meena1,2, Jarey H. Wang2,4, Nicholas J. Neill1,2,3, Dianne Keough8, Nagireddy Putluri5, Panagiotis Katsonis3, Amanda M. Koire3, Hyemin Lee6, Elizabeth A. Bowling1,2, Siddhartha Tyagi2, Mayra Orellana2, Rocio Dominguez-Vidaña2, Heyuan Li2, Kenneth Eagle3, Charles Danan3, Hsiang-Ching Chung2, Andrew D. Yang1,2,3,4, William Wu2,4, Sarah J. Kurley2, Brian M. Ho2,4,  \nJoseph R. Zoeller1,2,4, Calla M. Olson1,2, Kristen L. Meerbrey1,2, Olivier Lichtarge3, Arun Sreekumar5, Clifford C. Dacso5, Luke W. Guddat8, Dominik Rejman7, Dana Hocková7, Zlatko Janeba7,  \nLukas M. Simon1, Charles Y. Lin1,2,3,9, Monica C. Pillon1,2, and Thomas F. Westbrook1,2,3,9  \nUpregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes.  \nAlthough this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically.  \nSIgNIfICANCe: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers.  \nintRoduction  \nDuring tumorigenesis, cancer cells acquire genetic and epigenetic alterations that lead to widespread reprogramming of transcriptional and metabolic processes. Such changes fuel uncontrolled proliferation and other protumor hallmarks (1–6). However, large-scale deregulation of these processes may also create new dependencies and vulnerabilities in cancer cells (5, 7). In some cases, these counterbalancing protumor and stress hallmarks result from the same oncogenic alteration. MYC is a salient example of an oncogene that induces stresses across multiple cellular processes, from DNA replication to energy metabolism, that maybe exploited for anticancer therapies (8–12).  \nAmplification and/or hyperactivation of MYC occurs in 20% to 40% of human malignancies andisassociated with poor prognoses. As a transcription factor, MYC regulates many of its protumor functions by inducing or repressing gene expression programs (13–19) . Oncogenic MYC activation has also been shown to elevate total RNA and protein production in many disease contexts to support the metabolic demands of cell growth and proliferation; the mechanisms for this elevation in macromolecular synthesis are subjects of intensive study (20–30) .  \n1Therapeutic Innovation Center (THINC), Baylor College of Medicine, Houston, Texas. 2Verna & Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas. 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.  \n4Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas. 5Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. 6D","cbCairfqpjZAD84d","https://ap.wps.com/l/cbCairfqpjZAD84d","pdf",12912008,18,"English","# Introduction\n## MYC-driven transcriptional and metabolic reprogramming\n## RNA synthesis burden and RNA decay compensation\n# Discovery and mechanism\n## Cytoplasmic exosome-mediated RNA decay\n## DIS3L dependence and impact of exosome mutations\n# Therapeutic implications\n## Purine salvage as a compensatory pathway\n## Inhibiting purine salvage to impair MYC-driven progression","[{\"question\":\"How does MYC contribute to oncogenic stress in breast cancer cells?\",\"answer\":\"MYC increases cytoplasmic exosome-mediated RNA decay, leading to accumulation of cytotoxic RNA catabolites and reactive oxygen species. This RNA degradation and ribonucleotide catabolism trigger oncogenic cell death and stress.\"},{\"question\":\"What role do exosome mutations play in MYC-induced cell death?\",\"answer\":\"Tumor-derived exosome mutations can abrogate MYC-induced cell death, indicating that excess RNA decay is a toxic mechanism relevant to human cancers.\"},{\"question\":\"Why do purine salvage pathways matter for MYC-driven progression?\",\"answer\":\"Purine salvage compensates for MYC-induced ribonucleotide catabolism and mitigates its effects. Inhibitors of purine salvage impair MYC-positive tumor progression, suggesting a therapeutic vulnerability.\"}]","MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer | PDF",1789992424,45]