{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:49:51Z","timestamp":1792788591073,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014709","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000}}],"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BR3432\/7-1"],"award-info":[{"award-number":["BR3432\/7-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["STA357\/8-2"],"award-info":[{"award-number":["STA357\/8-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hertha-Nathorff-Programme of the University of Ulm","award":["LSSH.8000.13"],"award-info":[{"award-number":["LSSH.8000.13"]}],"id":[{"id":"https:\/\/ror.org\/032000t02","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Recent studies demonstrated that the structural maintenance of chromosomes complex 5\/6 (SMC5\/6) acts as an important antiviral restriction factor that silences episomal DNA. Consequently, viruses have evolved strategies to antagonize this defence system. Interestingly, it was shown that SMC5\/6-mediated silencing of extrachromosomal DNA depends on its recruitment to PML nuclear bodies (PML-NBs) which is mediated by a protein termed SMC5\/6 localization factor 2 (SLF2). Since human cytomegalovirus (HCMV) dissociates PML nuclear bodies during the first hours of infection, we asked for the fate of SMC5\/6 components during the HCMV replicative cycle. We first investigated the expression levels of SMC5\/6 core components at the onset of HCMV infection and found that they were not downregulated by HCMV. Instead, we observed a distinct decrease of SLF2 protein levels which correlated with a complete dispersal of the SMC5\/6 complex from PML-NBs. This was also observed after infection with UV-inactivated HCMV and could not be blocked by cycloheximide treatment suggesting the involvement of an imported structural component of the virion. While we could exclude a requirement of the HCMV tegument protein pp71 (UL82), a targeted screen identified the tegument protein UL35 as being required and sufficient for proteasomal degradation of SLF2. In line with these results, SLF2 levels remained stable after infection with a recombinant HCMV harbouring a stop codon within the UL35 gene region and this correlated with a defect in the onset of HCMV immediate early gene expression. Furthermore, we observed an enhanced recruitment of SMC5\/6 to PML-NBs and an overall increase in the association of parental viral genomes with SMC5\/6 containing PML-NBs in the absence of UL35. Congruently, siRNA mediated depletion of SLF2 resulted in a reversal of this phenotype. This strongly suggests that UL35 serves as a novel viral SLF2 antagonist to prevent the initial silencing of incoming viral genomes by SMC5\/6.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014709","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:42:21Z","timestamp":1791826941000},"page":"e1014709","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human cytomegalovirus antagonizes SMC5\/6 driven genome silencing via UL35 instituted proteasomal degradation of SLF2"],"prefix":"10.1371","volume":"22","author":[{"given":"Francesco","family":"Montagner","sequence":"first","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Scherer","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cora","family":"Stegmann","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich","family":"Hahn","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Ploil","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina Sandra","family":"Einsiedler","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Katharina","family":"Brosch","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Maeki","sequence":"additional","affiliation":[{"name":"Public Health Office, City of Sapporo","place":["Sapporo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramya","family":"Ramani","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universit\u00e4t Braunschweig","place":["Braunschweig, Germany"]},{"name":"Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research","place":["Braunschweig, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6420-1976","authenticated-orcid":true,"given":"Nicole","family":"Andr\u00e9e-Busch","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universit\u00e4t Braunschweig","place":["Braunschweig, Germany"]},{"name":"Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research","place":["Braunschweig, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie M.","family":"Brinkmann","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universit\u00e4t Braunschweig","place":["Braunschweig, Germany"]},{"name":"Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research","place":["Braunschweig, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9878-3119","authenticated-orcid":true,"given":"Thomas","family":"Stamminger","sequence":"additional","affiliation":[{"name":"Institute of Virology, Ulm University Medical Center","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"ppat.1014709.ref001","doi-asserted-by":"crossref","first-page":"102250","DOI":"10.1016\/j.coi.2022.102250","article-title":"Recent insights into innate immune nucleic acid sensing during viral infection","volume":"78","author":"C Guy","year":"2022","journal-title":"Curr Opin Immunol"},{"issue":"11","key":"ppat.1014709.ref002","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.tim.2022.05.004","article-title":"Nuclear antiviral innate responses at the intersection of DNA sensing and DNA repair","volume":"30","author":"JL Justice","year":"2022","journal-title":"Trends Microbiol"},{"issue":"3","key":"ppat.1014709.ref003","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1011180","article-title":"The SMC5\/6 complex: An emerging antiviral restriction factor that can silence episomal DNA","volume":"19","author":"ID Irwan","year":"2023","journal-title":"PLoS Pathog"},{"issue":"9","key":"ppat.1014709.ref004","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/s41594-022-00829-0","article-title":"Smc5\/6 silences episomal transcription by a three-step function","volume":"29","author":"F Abdul","year":"2022","journal-title":"Nat Struct Mol Biol"},{"key":"ppat.1014709.ref005","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-1-0716-4136-1_2","article-title":"Structural maintenance of chromosomes complexes","volume":"2856","author":"K Jeppsson","year":"2025","journal-title":"Methods in molecular biology"},{"issue":"7","key":"ppat.1014709.ref006","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/s41580-021-00349-7","article-title":"Genome folding through loop extrusion by SMC complexes","volume":"22","author":"IF Davidson","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"5","key":"ppat.1014709.ref007","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1093\/nar\/gkae103","article-title":"The SMC5\/6 complex: folding chromosomes back into shape when genomes take a break","volume":"52","author":"S Roy","year":"2024","journal-title":"Nucleic Acids Res"},{"issue":"20","key":"ppat.1014709.ref008","doi-asserted-by":"crossref","first-page":"12405","DOI":"10.1093\/nar\/gkae831","article-title":"Structural mechanisms of SLF1 interactions with Histone H4 and RAD18 at the stalled replication fork","volume":"52","author":"EL Ryder","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"ppat.1014709.ref009","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.106815.3","article-title":"SMC5\/6-mediated plasmid silencing is directed by SIMC1-SLF2 and antagonized by the SV40 large T antigen","volume":"14","author":"M Oravcov\u00e1","year":"2025","journal-title":"eLife"},{"issue":"19","key":"ppat.1014709.ref010","doi-asserted-by":"crossref","first-page":"12487","DOI":"10.1128\/JVI.79.19.12487-12494.2005","article-title":"Circularization of the herpes simplex virus type 1 genome upon lytic infection","volume":"79","author":"BL Strang","year":"2005","journal-title":"J Virol"},{"issue":"10","key":"ppat.1014709.ref011","doi-asserted-by":"crossref","first-page":"110411","DOI":"10.1016\/j.celrep.2022.110411","article-title":"Epstein-Barr virus BNRF1 destabilizes SMC5\/6 cohesin complexes to evade its restriction of replication compartments","volume":"38","author":"SPT Yiu","year":"2022","journal-title":"Cell Rep"},{"issue":"8","key":"ppat.1014709.ref012","article-title":"KSHV RTA antagonizes SMC5\/6 complex-induced viral chromatin compaction by hijacking the ubiquitin-proteasome system","volume":"18","author":"C Han","year":"2022","journal-title":"PLoS Pathog"},{"key":"ppat.1014709.ref013","unstructured":"Mocarski ES, Shenk T, Pass RF. Cytomegaloviruses. In DMKnipe and PMHowley (eds), Fields virologyLippincott\/The Williams and Wilkins Co, Philadelphia, PA. 2007:2701\u201372."},{"issue":"2","key":"ppat.1014709.ref014","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.virusres.2010.10.002","article-title":"Intrinsic cellular defense mechanisms targeting human cytomegalovirus","volume":"157","author":"N Tavalai","year":"2011","journal-title":"Virus Res"},{"key":"ppat.1014709.ref015","unstructured":"https:\/\/doi.org\/S0168-1702(10)00361-8 20934469"},{"issue":"13","key":"ppat.1014709.ref016","doi-asserted-by":"crossref","first-page":"5850","DOI":"10.1128\/JVI.01979-15","article-title":"Emerging Role of PML Nuclear Bodies in Innate Immune Signaling","volume":"90","author":"M Scherer","year":"2016","journal-title":"J Virol"},{"issue":"1","key":"ppat.1014709.ref017","doi-asserted-by":"crossref","first-page":"2321265","DOI":"10.1080\/19491034.2024.2321265","article-title":"PML Nuclear bodies: the cancer connection and beyond","volume":"15","author":"M Abou-Ghali","year":"2024","journal-title":"Nucleus"},{"key":"ppat.1014709.ref018","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.73006","article-title":"Dual signaling via interferon and DNA damage response elicits entrapment by giant PML nuclear bodies","volume":"11","author":"M Scherer","year":"2022","journal-title":"Elife"},{"issue":"8","key":"ppat.1014709.ref019","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1128\/JVI.80.8.3863-3871.2006","article-title":"Inactivating a cellular intrinsic immune defense mediated by Daxx is the mechanism through which the human cytomegalovirus pp71 protein stimulates viral immediate-early gene expression","volume":"80","author":"RT Saffert","year":"2006","journal-title":"J Virol"},{"issue":"24","key":"ppat.1014709.ref020","doi-asserted-by":"crossref","first-page":"12543","DOI":"10.1128\/JVI.01215-08","article-title":"Human cytomegalovirus protein pp71 displaces the chromatin-associated factor ATRX from nuclear domain 10 at early stages of infection","volume":"82","author":"V Lukashchuk","year":"2008","journal-title":"J Virol"},{"issue":"11","key":"ppat.1014709.ref021","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1004512","article-title":"Crystal structure of cytomegalovirus IE1 protein reveals targeting of TRIM family member PML via coiled-coil interactions","volume":"10","author":"M Scherer","year":"2014","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1014709.ref022","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1009863","article-title":"Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers","volume":"17","author":"J Schweininger","year":"2021","journal-title":"PLoS Pathog"},{"issue":"4","key":"ppat.1014709.ref023","article-title":"The Human Cytomegalovirus IE1 Protein Antagonizes PML Nuclear Body-Mediated Intrinsic Immunity via the Inhibition of PML De Novo SUMOylation","volume":"91","author":"E-M Schilling","year":"2017","journal-title":"J Virol"},{"issue":"1","key":"ppat.1014709.ref024","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1006\/excr.1996.0353","article-title":"The nuclear domain 10 (ND10) is disrupted by the human cytomegalovirus gene product IE1","volume":"229","author":"F Korioth","year":"1996","journal-title":"Exp Cell Res"},{"issue":"8","key":"ppat.1014709.ref025","doi-asserted-by":"crossref","first-page":"4899","DOI":"10.1128\/MCB.18.8.4899","article-title":"Disruption of PML subnuclear domains by the acidic IE1 protein of human cytomegalovirus is mediated through interaction with PML and may modulate a RING finger-dependent cryptic transactivator function of PML","volume":"18","author":"JH Ahn","year":"1998","journal-title":"Mol Cell Biol"},{"issue":"4","key":"ppat.1014709.ref026","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1042\/BST20221395","article-title":"SMC-based immunity against extrachromosomal DNA elements","volume":"51","author":"HW Liu","year":"2023","journal-title":"Biochem Soc Trans"},{"issue":"7","key":"ppat.1014709.ref027","article-title":"SLF2 Interacts with the SMC5\/6 Complex to Direct Hepatitis B Virus Episomal DNA to Promyelocytic Leukemia Bodies for Transcriptional Repression","volume":"97","author":"Q Yao","year":"2023","journal-title":"J Virol"},{"key":"ppat.1014709.ref028","first-page":"201","article-title":"Applications for a dual fluorescent human cytomegalovirus in the analysis of viral entry. Methods in molecular biology (Clifton, NJ)","volume":"1064","author":"KL Sampaio","year":"2013"},{"issue":"5","key":"ppat.1014709.ref029","article-title":"Structural mechanism of CRL4-instructed STAT2 degradation via a novel cytomegaloviral DCAF receptor","volume":"42","author":"VTK Le-Trilling","year":"2023","journal-title":"EMBO J"},{"issue":"3","key":"ppat.1014709.ref030","doi-asserted-by":"crossref","DOI":"10.1016\/j.chom.2018.07.011","article-title":"High-Definition Analysis of Host Protein Stability during Human Cytomegalovirus Infection Reveals Antiviral Factors and Viral Evasion Mechanisms","volume":"24","author":"K Nightingale","year":"2018","journal-title":"Cell Host Microbe"},{"issue":"6","key":"ppat.1014709.ref031","doi-asserted-by":"crossref","first-page":"790","DOI":"10.3390\/microorganisms8060790","article-title":"The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription","volume":"8","author":"M Fabits","year":"2020","journal-title":"Microorganisms"},{"issue":"5","key":"ppat.1014709.ref032","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1128\/jvi.76.5.2460-2468.2002","article-title":"The human cytomegalovirus UL35 gene encodes two proteins with different functions","volume":"76","author":"Y Liu","year":"2002","journal-title":"J Virol"},{"issue":"20","key":"ppat.1014709.ref033","doi-asserted-by":"crossref","first-page":"10960","DOI":"10.1128\/JVI.78.20.10960-10966.2004","article-title":"Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome","volume":"78","author":"SM Varnum","year":"2004","journal-title":"J Virol"},{"issue":"2","key":"ppat.1014709.ref034","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.virol.2011.03.013","article-title":"Nuclear body formation and PML body remodeling by the human cytomegalovirus protein UL35","volume":"414","author":"J Salsman","year":"2011","journal-title":"Virology"},{"issue":"5","key":"ppat.1014709.ref035","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1128\/JVI.79.5.3084-3096.2005","article-title":"Human cytomegalovirus tegument protein ppUL35 is important for viral replication and particle formation","volume":"79","author":"K Schierling","year":"2005","journal-title":"J Virol"},{"issue":"9","key":"ppat.1014709.ref036","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00013-18","article-title":"Interaction of Human Cytomegalovirus Tegument Proteins ppUL35 and ppUL35A with Sorting Nexin 5 Regulates Glycoprotein B (gpUL55) Localization","volume":"92","author":"G Maschkowitz","year":"2018","journal-title":"J Virol"},{"issue":"6","key":"ppat.1014709.ref037","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/s41594-023-01015-6","article-title":"The multi-functional Smc5\/6 complex in genome protection and disease","volume":"30","author":"XP Peng","year":"2023","journal-title":"Nat Struct Mol Biol"},{"issue":"7594","key":"ppat.1014709.ref038","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/nature17170","article-title":"Hepatitis B virus X protein identifies the Smc5\/6 complex as a host restriction factor","volume":"531","author":"A Decorsi\u00e8re","year":"2016","journal-title":"Nature"},{"issue":"1","key":"ppat.1014709.ref039","doi-asserted-by":"crossref","first-page":"7805","DOI":"10.1038\/s41467-024-50646-w","article-title":"Human Smc5\/6 recognises transcription-generated positive DNA supercoils","volume":"15","author":"A Diman","year":"2024","journal-title":"Nat Commun"},{"issue":"6","key":"ppat.1014709.ref040","doi-asserted-by":"crossref","DOI":"10.1016\/j.molcel.2020.11.011","article-title":"The Smc5\/6 core complex is a structure-specific DNA binding and compacting machine","volume":"80","author":"D Serrano","year":"2020","journal-title":"Molecular Cell"},{"issue":"11","key":"ppat.1014709.ref041","doi-asserted-by":"crossref","first-page":"2846","DOI":"10.1016\/j.celrep.2016.08.026","article-title":"Hepatitis B Virus X Protein Promotes Degradation of SMC5\/6 to Enhance HBV Replication","volume":"16","author":"CM Murphy","year":"2016","journal-title":"Cell Reports"},{"issue":"11","key":"ppat.1014709.ref042","article-title":"Adenovirus E1B-55K controls SUMO-dependent degradation of antiviral cellular restriction factors","volume":"97","author":"W-H Ip","year":"2023","journal-title":"J Virol"},{"issue":"6234","key":"ppat.1014709.ref043","doi-asserted-by":"crossref","first-page":"1253671","DOI":"10.1126\/science.1253671","article-title":"DNA repair. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links","volume":"348","author":"M R\u00e4schle","year":"2015","journal-title":"Science"},{"issue":"1","key":"ppat.1014709.ref044","doi-asserted-by":"crossref","first-page":"6664","DOI":"10.1038\/s41467-022-34349-8","article-title":"Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy","volume":"13","author":"LJ Grange","year":"2022","journal-title":"Nat Commun"},{"issue":"11","key":"ppat.1014709.ref045","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1016\/j.bbamcr.2008.08.004","article-title":"New insights into the role of the subnuclear structure ND10 for viral infection","volume":"1783","author":"N Tavalai","year":"2008","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"ppat.1014709.ref046","article-title":"The Smc5\/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection","volume":"12","author":"C Niu","year":"2017","journal-title":"PLoS One"},{"issue":"5","key":"ppat.1014709.ref047","doi-asserted-by":"crossref","DOI":"10.1016\/j.chom.2021.03.001","article-title":"The SMC5\/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr","volume":"29","author":"L Dupont","year":"2021","journal-title":"Cell Host Microbe"},{"issue":"2","key":"ppat.1014709.ref048","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1128\/jvi.62.2.427-434.1988","article-title":"trans-activation of viral enhancers by the hepatitis B virus X protein","volume":"62","author":"DF Spandau","year":"1988","journal-title":"J Virol"},{"issue":"2","key":"ppat.1014709.ref049","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/j.1460-2075.1990.tb08136.x","article-title":"The hepatitis B virus X-gene product trans-activates both RNA polymerase II and III promoters","volume":"9","author":"B Aufiero","year":"1990","journal-title":"EMBO J"},{"issue":"6","key":"ppat.1014709.ref050","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1002\/hep.25928","article-title":"Hepatitis B virus X protein stimulates gene expression selectively from extrachromosomal DNA templates","volume":"56","author":"PC van Breugel","year":"2012","journal-title":"Hepatology"},{"issue":"17","key":"ppat.1014709.ref051","doi-asserted-by":"crossref","first-page":"9512","DOI":"10.1128\/JVI.78.17.9512-9523.2004","article-title":"Human cytomegalovirus tegument proteins ppUL82 (pp71) and ppUL35 interact and cooperatively activate the major immediate-early enhancer","volume":"78","author":"K Schierling","year":"2004","journal-title":"J Virol"},{"issue":"11","key":"ppat.1014709.ref052","doi-asserted-by":"crossref","first-page":"5769","DOI":"10.1128\/JVI.76.11.5769-5783.2002","article-title":"Functional interaction between the pp71 protein of human cytomegalovirus and the PML-interacting protein human Daxx","volume":"76","author":"H Hofmann","year":"2002","journal-title":"J Virol"},{"issue":"24","key":"ppat.1014709.ref053","doi-asserted-by":"crossref","first-page":"12543","DOI":"10.1128\/JVI.01215-08","article-title":"Human cytomegalovirus protein pp71 displaces the chromatin-associated factor ATRX from nuclear domain 10 at early stages of infection","volume":"82","author":"V Lukashchuk","year":"2008","journal-title":"J Virol"},{"issue":"4","key":"ppat.1014709.ref054","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1093\/nar\/gkw012","article-title":"New players in heterochromatin silencing: histone variant H3.3 and the ATRX\/DAXX chaperone","volume":"44","author":"HPJ Voon","year":"2016","journal-title":"Nucleic Acids Res"},{"issue":"24","key":"ppat.1014709.ref055","doi-asserted-by":"crossref","first-page":"9575","DOI":"10.1073\/pnas.1207496109","article-title":"BclAF1 restriction factor is neutralized by proteasomal degradation and microRNA repression during human cytomegalovirus infection","volume":"109","author":"SH Lee","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"ppat.1014709.ref056","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1002376","article-title":"EBV tegument protein BNRF1 disrupts DAXX-ATRX to activate viral early gene transcription","volume":"7","author":"K Tsai","year":"2011","journal-title":"PLoS Pathog"},{"issue":"2","key":"ppat.1014709.ref057","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1128\/JVI.05442-11","article-title":"Proteomic profiling of the human cytomegalovirus UL35 gene products reveals a role for UL35 in the DNA repair response","volume":"86","author":"J Salsman","year":"2012","journal-title":"J Virol"},{"issue":"40","key":"ppat.1014709.ref058","doi-asserted-by":"crossref","first-page":"42590","DOI":"10.18632\/oncotarget.6052","article-title":"The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications","volume":"6","author":"Y Sang","year":"2015","journal-title":"Oncotarget"},{"issue":"2","key":"ppat.1014709.ref059","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.3003621","article-title":"DNA damage induced by HIV-1 Vpr triggers epigenetic remodeling and transcriptional programs to enhance virus transcription and latency reactivation","volume":"24","author":"N Saladino","year":"2026","journal-title":"PLoS Biol"},{"issue":"20","key":"ppat.1014709.ref060","article-title":"Human Cytomegalovirus Utilizes Multiple Viral Proteins to Regulate the Basement Membrane Protein Nidogen 1","volume":"96","author":"MI Kuan","year":"2022","journal-title":"J Virol"},{"issue":"5","key":"ppat.1014709.ref061","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.01718-22","article-title":"HCMV infection reduces nidogen-1 expression, contributing to impaired neural rosette development in brain organoids","volume":"97","author":"EC Ijezie","year":"2023","journal-title":"J Virol"},{"issue":"2","key":"ppat.1014709.ref062","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1073\/pnas.97.2.853","article-title":"Specific chromosome 1 breaks induced by human cytomegalovirus","volume":"97","author":"EA Fortunato","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"ppat.1014709.ref063","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.1128\/JVI.74.6.2510-2524.2000","article-title":"Covalent modification of the transactivator protein IE2-p86 of human cytomegalovirus by conjugation to the ubiquitin-homologous proteins SUMO-1 and hSMT3b","volume":"74","author":"H Hofmann","year":"2000","journal-title":"J Virol"},{"issue":"5","key":"ppat.1014709.ref064","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1128\/jvi.65.5.2273-2282.1991","article-title":"Discordant expression of the immediate-early 1 and 2 gene regions of human cytomegalovirus at early times after infection involves posttranscriptional processing events","volume":"65","author":"T Stamminger","year":"1991","journal-title":"J Virol"},{"issue":"2","key":"ppat.1014709.ref065","doi-asserted-by":"crossref","first-page":"191","DOI":"10.2144\/000112096","article-title":"Two-step red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli","volume":"40","author":"BK Tischer","year":"2006","journal-title":"Biotechniques"},{"issue":"7","key":"ppat.1014709.ref066","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.3390\/v14071561","article-title":"Viral and Cellular Factors Contributing to the Hematogenous Dissemination of Human Cytomegalovirus via Polymorphonuclear Leukocytes","volume":"14","author":"B Braun","year":"2022","journal-title":"Viruses"},{"issue":"1","key":"ppat.1014709.ref067","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1013856","article-title":"Exonuclease ISG20 inhibits human cytomegalovirus replication by inducing an innate immune defense signature","volume":"22","author":"M Hehl","year":"2026","journal-title":"PLoS Pathog"},{"issue":"6","key":"ppat.1014709.ref068","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.02346-20","article-title":"The Autophagy-Initiating Protein Kinase ULK1 Phosphorylates Human Cytomegalovirus Tegument Protein pp28 and Regulates Efficient Virus Release","volume":"95","author":"P K\u00f6nig","year":"2021","journal-title":"J Virol"},{"issue":"1","key":"ppat.1014709.ref069","doi-asserted-by":"crossref","first-page":"4591","DOI":"10.1038\/s41467-023-40217-w","article-title":"The HSV-1 ICP22 protein selectively impairs histone repositioning upon Pol II transcription downstream of genes","volume":"14","author":"L Djakovic","year":"2023","journal-title":"Nat Commun"},{"issue":"8","key":"ppat.1014709.ref070","article-title":"The chromatin remodeling protein ATRX positively regulates IRF3-dependent type I interferon production and interferon-induced gene expression","volume":"18","author":"A-C Stilp","year":"2022","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1014709.ref071","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.3390\/v14081626","article-title":"Cross-Species Analysis of Innate Immune Antagonism by Cytomegalovirus IE1 Protein","volume":"14","author":"F Rothemund","year":"2022","journal-title":"Viruses"},{"issue":"7","key":"ppat.1014709.ref072","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"J Schindelin","year":"2012","journal-title":"Nat Methods"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1014709","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014709","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:43:40Z","timestamp":1792691020000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014709"}},"subtitle":[],"editor":[{"given":"Eain A","family":"Murphy","sequence":"first","affiliation":[{"name":"State University of New York Upstate Medical University","place":["UNITED STATES OF AMERICA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,12]]},"references-count":72,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1014709","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,12]]}}}