{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CPSF3 (also known as CPSF‐73) is the core, zinc‐dependent endonuclease of the cleavage and polyadenylation machinery that executes 3′–end processing of nascent mRNAs. Structural and functional studies have shown that CPSF3 directly associates with other CPSF subunits to recognize the polyadenylation signal and to cleave pre‐mRNAs at a defined site, thereby generating the substrate for polyadenylation (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In addition to its well‐established role in processing conventional polyadenylated mRNAs, CPSF3 is recruited in specialized ribonucleoprotein complexes to process non–polyadenylated transcripts such as replication‐dependent histone pre–mRNAs. Here, the U7 snRNP and its associated factors (including FLASH and Lsm11) guide CPSF3 to catalyze the endonucleolytic cleavage that not only generates the mature histone mRNA but also promotes subsequent degradation of downstream cleavage products."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Furthermore, CPSF3‐like activities are integral to other RNA–processing assemblies – for instance, within the Integrator complex the CPSF73 paralogue (INTS11), partnered with INTS9, performs analogous endonucleolytic functions for snRNA 3′–end maturation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Importantly, CPSF3 also emerges as a regulatory nexus in cancer. In colorectal carcinoma, for example, CPSF3 was found to interact with the long noncoding RNA CASC9, and its knockdown recapitulated the tumor–suppressive effects observed upon CASC9 depletion by modulating the stability of transcripts such as those encoding TGFβ2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In a related oncogenic context, binding of the tumor suppressor CSR1 to CPSF3 causes its mislocalization from the nucleus to the cytoplasm, thereby inhibiting global polyadenylation and triggering cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Collectively, these findings underscore CPSF3’s essential role as the catalytic engine of pre–mRNA cleavage during 3′–end formation, as well as its involvement in specialized RNA processing pathways and in the regulation of gene expression programs that impact cell proliferation and oncogenesis.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Corey R Mandel, Syuzo Kaneko, Hailong Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature05363"}], "href": "https://doi.org/10.1038/nature05363"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17128255"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17128255"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Nikolay G Kolev, Therese A Yario, Eleni Benson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3'-end maturation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/embor.2008.146"}], "href": "https://doi.org/10.1038/embor.2008.146"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18688255"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18688255"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Rakesh S Laishram, Richard A Anderson "}, {"type": "b", "children": [{"type": "t", "text": "The poly A polymerase Star-PAP controls 3'-end cleavage by promoting CPSF interaction and specificity toward the pre-mRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2010.287"}], "href": "https://doi.org/10.1038/emboj.2010.287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21102410"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21102410"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xiao-Cui Yang, Brandon D Burch, Yan Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FLASH, a proapoptotic protein involved in activation of caspase-8, is essential for 3' end processing of histone pre-mRNAs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2009.08.016"}], "href": "https://doi.org/10.1016/j.molcel.2009.08.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19854135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19854135"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yixuan Wu, Todd R Albrecht, David Baillat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular basis for the interaction between Integrator subunits IntS9 and IntS11 and its functional importance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1616605114"}], "href": "https://doi.org/10.1073/pnas.1616605114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28396433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28396433"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Todd R Albrecht, Sergey P Shevtsov, Yixuan Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrator subunit 4 is a 'Symplekin-like' scaffold that associates with INTS9/11 to form the Integrator cleavage module."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gky100"}], "href": "https://doi.org/10.1093/nar/gky100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29471365"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29471365"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kaili Luo, Jingwen Geng, Qinkai Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA CASC9 interacts with CPSF3 to regulate TGF-β signaling in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Clin Cancer Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13046-019-1263-3"}], "href": "https://doi.org/10.1186/s13046-019-1263-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31186036"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31186036"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Z-H Zhu, Y P Yu, Y-K Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CSR1 induces cell death through inactivation of CPSF3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2008.359"}], "href": "https://doi.org/10.1038/onc.2008.359"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18806823"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18806823"}]}]}]}