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Reconstituting miR-4638-5p drives synthetic lethality in BRCA1-deficient cancer cells by repressing TATDN2, an under-characterized TATD nuclease family member. Human TATDN2 cleaves and degrades RNA strands from double-stranded hairpin RNA and can resolve R-loops in a Mg2+-dependent in vitro assay. TATDN2 depletion increases R-loops, DNA damage, and chromosomal instability and impairs replication fork progression. Functionally, TATDN2 is essential for survival of BRCA1-deficient but not BRCA1-repleted cells, supporting therapeutic targeting.",{"@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/tatdn2-resolution-of-r-loops-is-required-for-survival-of-brca1-mutant-cancer-cells/381932/",{"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/tatdn2-resolution-of-r-loops-is-required-for-survival-of-brca1-mutant-cancer-cells/381932.png","ImageObject",300,407,{"name":92,"@type":93},"Anna Hans","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does miR-4638-5p affect BRCA1-deficient cancer cells?","Question",{"text":112,"@type":113},"Reconstituting miR-4638-5p causes synthetic lethality in BRCA1-deficient cancer cells.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What biochemical activity does TATDN2 have on RNA and R-loops?",{"text":117,"@type":113},"TATDN2 binds R-loops and degrades the RNA strand (not DNA) from multiple R-loop forms in vitro in a Mg2+-dependent manner.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is TATDN2 important specifically for BRCA1-deficient cells?",{"text":121,"@type":113},"Loss of TATDN2 increases cellular R-loops, DNA damage, and chromosomal instability, and the authors find TATDN2 is essential for survival of BRCA1-deficient cancer cells but much less so when BRCA1 is repleted.","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},381932,1790557920,{"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":8,"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},5909892332657,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","TATDN2 resolution of R-loops is required for survival of BRCA1-mutant cancer cells  \nAruna S. Jaiswal1 , Arijit Dutta2 , Gayathri Srinivasan 1 , Yaxia Yuan2 , Daohong Zhou2 , Montaser Shaheen1 , Doraid T. Sadideen 1 , Austin Kirby 1 , Elizabeth A. Williamson 1 ,  \nYogesh K. Gupta 2 , Shaun K. Olsen2 , Mingjiang Xu3 , Eva Loranc4 , Pramiti Mukhopadhyay4 , Alexander Pertsemlidis 4 , Alexander J.R. Bishop 4 , Patrick Sung2 , Jac A. Nickoloff 5 , * and Robert Hromas 1 , *  \n1 Department of Medicine and the Mays Cancer Center, the University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA  \n2 Department of Biochemistry and Structural Biology and the Greehey Children’s Cancer Research Institute, the University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA  \n3 Department of Molecular Medicine and the Mays Cancer Center, the University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA  \n4 Department of Cell Systems and Anatomy and the Greehey Children’s Cancer Research Institute, the University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA  \n5 Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA  \n* To whom correspondence should be addressed. Tel: +1 210 567 4432; Email: [hromas@uthscsa.edu](hromas@uthscsa.edu)[ ](hromas@uthscsa.edu)Correspondence may also be addressed to Jac A. Nickoloff. Tel: +1 970 491 6674; Email: [J.Nickoloff@colostate.edu](J.Nickoloff@colostate.edu)  \nAbstract  \nBRCA1-deficient cells have increased IRE1 RNase, which degrades multiple microRNAs. Reconstituting expression of one of these, miR-4638– 5p, resulted in synthetic lethality in BRCA1-deficient cancer cells. We found that miR-4638-5p represses expression of TATDN2, a poorly characterized member of the TATD nuclease family. We discovered that human TATDN2 has RNA 3􀀂 exonuclease and endonuclease activity on double-stranded hairpin RNA structures. Given the cleavage of hairpin RNA by TATDN2, and that BRCA1-deficient cells have difficulty resolving R-loops, we tested whether TATDN2 could resolve R-loops. Using in vitro biochemical reconstitution assays, we found TATDN2 bound to R-loopsand degraded the RNA strand but not DNA of multiple forms of R-loops in vitro in a Mg2+-dependent manner. Mutations in amino acids E593 and E705 predicted by Alphafold-2 to chelate an essential Mg2+ cation completely abrogated this R-loop resolution activity. Depleting TATDN2 increased cellular R-loops, DNA damage and chromosomal instability. Loss of TATDN2 resulted in poor replication fork progression in the presence of increased R-loops. Significantly, we found that TATDN2 is essential for survival of BRCA1-deficient cancer cells, but much less so for cognate BRCA1-repleted cancer cells. Thus, we propose that TATDN2 is a novel target for therapy of BRCA1-deficient cancers.  \nGraphical abstract  \nReceived: May 28, 2023. Revised: October 3, 2023. Editorial Decision: October 8, 2023. Accepted: October 18, 2023  \n© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License  \n([http:](http://creativecommons.org/licenses/by-nc/4.0/)[//](http://creativecommons.org/licenses/by-nc/4.0/)[creativecommons.org](http://creativecommons.org/licenses/by-nc/4.0/)[/](http://creativecommons.org/licenses/by-nc/4.0/)[licenses](http://creativecommons.org/licenses/by-nc/4.0/)[/](http://creativecommons.org/licenses/by-nc/4.0/)[by-nc](http://creativecommons.org/licenses/by-nc/4.0/)[/](http://creativecommons.org/licenses/by-nc/4.0/)[4.0](http://creativecommons.org/licenses/by-nc/4.0/)[/](http://creativecommons.org/licenses/by-nc/4.0/)), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original wor","cbCairf7MZcyw0cd","https://ap.wps.com/l/cbCairf7MZcyw0cd","pdf",1880333,18,"English","# Abstract\n# Introduction","[{\"question\":\"How does miR-4638-5p affect BRCA1-deficient cancer cells?\",\"answer\":\"Reconstituting miR-4638-5p causes synthetic lethality in BRCA1-deficient cancer cells.\"},{\"question\":\"What biochemical activity does TATDN2 have on RNA and R-loops?\",\"answer\":\"TATDN2 binds R-loops and degrades the RNA strand (not DNA) from multiple R-loop forms in vitro in a Mg2+-dependent manner.\"},{\"question\":\"Why is TATDN2 important specifically for BRCA1-deficient cells?\",\"answer\":\"Loss of TATDN2 increases cellular R-loops, DNA damage, and chromosomal instability, and the authors find TATDN2 is essential for survival of BRCA1-deficient cancer cells but much less so when BRCA1 is repleted.\"}]","TATDN2 resolution of R-loops is required for survival of BRCA1-mutant cancer cells | PDF",1790247863,45]