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While previous studies have characterized ZFP809 as responsible for binding and repressing ERVs containing a proline tRNA primer-binding site (PBS-Pro) in mice, comparable KZFPs have not been identified in humans yet. Here, we identified ZNF506 as a PBS-Pro-binding protein in humans, which functions as a transcriptional repressor of PBS-Pro-utilizing retroviruses by recruiting heterochromatic modifications. Although they have similar functions, the low protein similarities between ZNF506, ZFP809 and KZFPs of other species suggest their independent evolution against the invasion of PBS-Pro-utilizing retroviruses into their respective ancestor genomes after species divergence. We also explored the link between ZNF506 and leukemia. Our findings suggest that ZNF506 is a unique human KZFP that can bind to PBS-Pro, highlighting the diverse evolution of KZFPs in defending against retroviral invasions. Additionally, our study provides insights into the potential role of ZNF506 in leukemia, contributing to the expanding knowledge of KZFPs' crucial function in disease and genome stability.<\/jats:p>","DOI":"10.1093\/nar\/gkad731","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T10:13:29Z","timestamp":1692699209000},"page":"10309-10325","source":"Crossref","is-referenced-by-count":7,"title":["Unraveling the role of ZNF506 as a human PBS-pro-targeting protein for ERVP repression"],"prefix":"10.1093","volume":"51","author":[{"given":"Qian","family":"Wu","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Life Sciences and Technology, Tongji University , Shanghai\u00a0 200092 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Fang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Life Sciences and Technology, Tongji University , Shanghai\u00a0 200092 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University , Shanghai\u00a0 200092 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9724-7936","authenticated-orcid":false,"given":"Peng","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Life Sciences and Technology, Tongji University , Shanghai\u00a0 200092 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,9,11]]},"reference":[{"key":"2023102701560387600_B1","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.tig.2017.08.006","article-title":"The role of KRAB-ZFPs in transposable element repression and mammalian evolution","volume":"33","author":"Yang","year":"2017","journal-title":"Trends Genet."},{"key":"2023102701560387600_B2","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1242\/dev.132605","article-title":"KRAB zinc finger proteins","volume":"144","author":"Ecco","year":"2017","journal-title":"Development"},{"key":"2023102701560387600_B3","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1101\/gad.10.16.2067","article-title":"KAP-1, a novel corepressor for the highly conserved KRAB repression domain","volume":"10","author":"Friedman","year":"1996","journal-title":"Genes Dev."},{"key":"2023102701560387600_B4","doi-asserted-by":"crossref","first-page":"26267","DOI":"10.1074\/jbc.R111.252569","article-title":"KAP1 protein: an enigmatic master regulator of the genome","volume":"286","author":"Iyengar","year":"2011","journal-title":"J. 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Chem."},{"key":"2023102701560387600_B5","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1101\/gad.973302","article-title":"SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins","volume":"16","author":"Schultz","year":"2002","journal-title":"Genes Dev."},{"key":"2023102701560387600_B6","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1101\/gad.869501","article-title":"Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the mi-2alpha subunit of NuRD","volume":"15","author":"Schultz","year":"2001","journal-title":"Genes Dev."},{"key":"2023102701560387600_B7","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1101\/gad.1102803","article-title":"Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation","volume":"17","author":"Ayyanathan","year":"2003","journal-title":"Genes Dev."},{"key":"2023102701560387600_B8","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.celrep.2012.08.043","article-title":"The KRAB-ZFP\/KAP1 system contributes to the early embryonic establishment of site-specific DNA methylation patterns maintained during development","volume":"2","author":"Quenneville","year":"2012","journal-title":"Cell Rep."},{"key":"2023102701560387600_B9","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/gb-2003-4-10-231","article-title":"KRAB-containing zinc-finger repressor proteins","volume":"4","author":"Urrutia","year":"2003","journal-title":"Genome Biol."},{"key":"2023102701560387600_B10","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1038\/nature07844","article-title":"Embryonic stem cells use ZFP809 to silence retroviral DNAs","volume":"458","author":"Wolf","year":"2009","journal-title":"Nature"},{"key":"2023102701560387600_B11","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/PL00000885","article-title":"Three classes of C2H2 zinc finger proteins","volume":"58","author":"Iuchi","year":"2001","journal-title":"Cell. 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