{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZinc finger CCCH-type containing protein 14 (ZC3H14) is an evolutionarily conserved polyadenosine RNA binding protein that employs a unique tandem CCCH zinc finger motif to selectively recognize poly(A) RNA. Initial studies in yeast, where the protein is known as Nab2, and subsequent work in human neuronal tissues have established ZC3H14 as a critical regulator of post‐transcriptional gene expression. Notably, mutations in ZC3H14 have been linked to autosomal recessive nonsyndromic intellectual disability, underscoring its importance in neural development and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n \nDissection of ZC3H14 function in mammalian systems has revealed that it exists in multiple alternatively spliced isoforms exhibiting distinct subcellular localizations. The predominant isoforms possess classical nuclear localization signals and localize to nuclear speckles where they colocalize with splicing factors, suggesting roles in mRNA processing. ZC3H14 is integral to the regulation of poly(A) tail length and nuclear retention of pre-mRNAs, exemplified by its control over the steady-state levels and turnover of transcripts such as ATP5G1—a key component in cellular energy homeostasis. These studies collectively argue that ZC3H14 fine-tunes mRNA maturation and processing in a transcript-specific manner, particularly in neurons."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n\nEmerging evidence further implicates the dysregulation of ZC3H14 and its orthologs in neurodegeneration and cancer. In tauopathy models, alterations in the activity of related RNA binding proteins—such as the mammalian homolog MSUT2—are shown to influence tau aggregation and toxicity, suggesting that proper poly(A) RNA processing protects neurons from tau-induced damage. Complementary genetic screens in Caenorhabditis elegans have identified sut-2, a functional analog, as a modulator of tau pathology. In parallel, studies in hepatocellular carcinoma indicate that reduced ZC3H14 expression contributes to tumor progression via deregulation of integrin pathway signaling, marking it as a potential tumor suppressor. These findings collectively support the concept that targeting the functions of ZC3H14 and related poly(A) RNA binding proteins may provide novel therapeutic avenues for both tauopathies and certain cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Seth M Kelly, Suzette A Pabit, Chad M Kitchen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recognition of polyadenosine RNA by zinc finger proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0701244104"}], "href": "https://doi.org/10.1073/pnas.0701244104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17630287"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17630287"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Changhui Pak, Masoud Garshasbi, Kimia Kahrizi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation of the conserved polyadenosine RNA binding protein, ZC3H14/dNab2, impairs neural function in Drosophila and humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1107103108"}], "href": "https://doi.org/10.1073/pnas.1107103108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21734151"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21734151"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Seth M Kelly, Sara W Leung, ChangHui Pak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A conserved role for the zinc finger polyadenosine RNA binding protein, ZC3H14, in control of poly(A) tail length."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "RNA (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1261/rna.043984.113"}], "href": "https://doi.org/10.1261/rna.043984.113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24671764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24671764"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Sara W Leung, Luciano H Apponi, Omar E Cornejo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Splice variants of the human ZC3H14 gene generate multiple isoforms of a zinc finger polyadenosine RNA binding protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2009.02.022"}], "href": "https://doi.org/10.1016/j.gene.2009.02.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19303045"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19303045"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Callie P Wigington, Kevin J Morris, Laura E Newman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Polyadenosine RNA-binding Protein, Zinc Finger Cys3His Protein 14 (ZC3H14), Regulates the Pre-mRNA Processing of a Key ATP Synthase Subunit mRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M116.754069"}], "href": "https://doi.org/10.1074/jbc.M116.754069"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27563065"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27563065"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Chris R Guthrie, Lynne Greenup, James B Leverenz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MSUT2 is a determinant of susceptibility to tau neurotoxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr079"}], "href": "https://doi.org/10.1093/hmg/ddr079"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21355046"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21355046"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jeanna M Wheeler, Chris R Guthrie, Brian C Kraemer "}, {"type": "b", "children": [{"type": "t", "text": "The role of MSUT-2 in tau neurotoxicity: a target for neuroprotection in tauopathy?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Soc Trans (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BST0380973"}], "href": "https://doi.org/10.1042/BST0380973"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20658987"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20658987"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Chuxiao Zhang, Pengbo Cao, Aiqing Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of ZC3H14 driven by chromosome 14q31 deletion promotes hepatocellular carcinoma progression by activating integrin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgy146"}], "href": "https://doi.org/10.1093/carcin/bgy146"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30371740"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30371740"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jeremy D Baker, Rikki L Uhrich, Timothy J Strovas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AlphaScreen Identifies MSUT2 Inhibitors for Tauopathy-Targeting Therapeutic Discovery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "SLAS Discov (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/2472555220958387"}], "href": "https://doi.org/10.1177/2472555220958387"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32981422"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32981422"}]}]}]}