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PPM1D, a master negative regulator of the response, is commonly amplified or activated by gain-of-function mutations across multiple human cancers, supporting its relevance as a pharmacological target. Using CRISPR/Cas9 screening, researchers identified synthetic-lethal dependencies of PPM1D, highlighting superoxide dismutase-1 (SOD1) as a potential vulnerability in PPM1D-mutant cells. The study uncovers increased reactive oxygen species and impaired oxidative stress response, supporting SOD1’s role in survival and suggesting a therapeutic strategy.",{"@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":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/sod1-is-a-synthetic-lethal-target-in-ppm1d-mutant-leukemia-cells/332159/",{"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/sod1-is-a-synthetic-lethal-target-in-ppm1d-mutant-leukemia-cells/332159.png","ImageObject",300,407,{"name":92,"@type":93},"Violet","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main biological role of PPM1D in cancer-related DNA damage response?","Question",{"text":112,"@type":113},"PPM1D acts as a master negative regulator that helps terminate the DNA damage response by dephosphorylating multiple DDR signaling molecules. Gain-of-function mutations and amplifications of PPM1D are found across human cancers.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were synthetic-lethal dependencies of PPM1D identified?",{"text":117,"@type":113},"The study used CRISPR/Cas9 screening to uncover dependencies that become lethal when paired with specific PPM1D mutant contexts.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is SOD1 considered a potential target in PPM1D-mutant leukemia cells?",{"text":121,"@type":113},"Loss of SOD1 is synthetic lethal with PPM1D mutation. The results also show a dysregulated redox state with elevated reactive oxygen species and a compromised oxidative stress response, supporting SOD1’s role in survival.","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},332159,1790189345,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},4398048950312,"https://ap-avatar.wpscdn.com/avatar/400002538284de19e3c?_k=1778320343897328908","RESEARCH ARTICLE  \n*For correspondence:  \n[goodell@bcm.edu](goodell@bcm.edu)  \nCompeting interest: The authors declare that no competing interests exist.  \nFunding: See page 20  \nSent for Review  \n11 August 2023  \nPreprint posted  \n01 September 2023  \nReviewed preprint posted  \n04 October 2023  \nReviewed preprint revised  \n04 April 2024  \nVersion of Record published  \n18 June 2024  \nReviewing Editor: Libor Macurek, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Czech Republic  \n This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.  \nSOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells  \nLinda Zhang1,2,3,4,5, Joanne I Hsu1,2,3, Etienne D Braekeleer6, Chun-Wei Chen3,4,5,7, Tajhal D Patel8, Alejandra G Martell4, Anna G Guzman4, Katharina Wohlan4, Sarah M Waldvogel2,3,4,5,9, Hidetaka Uryu10, Ayala Tovy3,4,5, Elsa Callen11, Rebecca L Murdaugh3,4,5,12, Rosemary Richard3,4,5,12, Sandra Jansen13,  \nLisenka Vissers13, Bert BA de Vries13, Andre Nussenzweig11, Shixia Huang4,14, Cristian Coarfa4, Jamie Anastas3,4,5,12, Koichi Takahashi10,15, George Vassiliou6, Margaret A Goodell3,4,5*  \n1Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, United States; 2 Medical Scientist Training Program, Baylor College of Medicine, Houston, United States; 3Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; 5Center for Cell and Gene Therapy, Houston, United States; 6 Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; 7 Integrated Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, United States; 8Texas Children’s Hospital Department of Hematology/Oncology, Baylor College of Medicine, Houston, United States; 9Cancer and Cell Biology Graduate Program, Baylor College of Medicine, Houston, United States; 10 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States; 11 Laboratory of Genome Integrity, National Cancer Institute, National Institute of Health, Bethesda, United States; 12 Department of Neurosurgery, Baylor College of Medicine, Houston, United States; 13 Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands; 14 Department of Education, Innovation and Technology, Advanced Technology Cores, University of Texas, Houston, United States; 15 Department of Genome Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States  \nAbstract The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+ -dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight anew potential therapeutic strategy against PPM1D-mutant cancers.  \nZhang et al. eLife 2023;12:RP91611. DOI: [https://doi.org/10.7554/eLife.91611](https://doi.org/10.7554/eLife.91611) 1 of 26  \n Research article Cancer Biology | Cell Biology  \neLife assessment  \nGain-of","cbCaiu9gW6cRlF7d","https://ap.wps.com/l/cbCaiu9gW6cRlF7d","pdf",1628113,26,"English","# Abstract\n## PPM1D in DNA damage response and cancer\n## CRISPR/Cas9 identification of synthetic-lethal dependencies\n## SOD1 vulnerability in PPM1D-mutant leukemia cells\n## Redox imbalance and oxidative stress response\n## Implications for therapy","[{\"question\":\"What is the main biological role of PPM1D in cancer-related DNA damage response?\",\"answer\":\"PPM1D acts as a master negative regulator that helps terminate the DNA damage response by dephosphorylating multiple DDR signaling molecules. Gain-of-function mutations and amplifications of PPM1D are found across human cancers.\"},{\"question\":\"How were synthetic-lethal dependencies of PPM1D identified?\",\"answer\":\"The study used CRISPR/Cas9 screening to uncover dependencies that become lethal when paired with specific PPM1D mutant contexts.\"},{\"question\":\"Why is SOD1 considered a potential target in PPM1D-mutant leukemia cells?\",\"answer\":\"Loss of SOD1 is synthetic lethal with PPM1D mutation. The results also show a dysregulated redox state with elevated reactive oxygen species and a compromised oxidative stress response, supporting SOD1’s role in survival.\"}]","SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells | PDF",1789997091,66]