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This transport through the nuclear envelope requires homologs of the conserved herpesviral pUL31 and pUL34 proteins which form the nuclear egress complex (NEC). In its absence, 1,000-fold less virus progeny is produced. We isolated a UL34-negative mutant of the alphaherpesvirus pseudorabies virus (PrV), PrV-\u0394UL34Pass, which regained replication competence after serial passages in cell culture by inducing nuclear envelope breakdown (NEBD) (B. G. Klupp, H. Granzow, and T. C. Mettenleiter, J. Virol. 85:8285\u20138292, 2011). To test whether this phenotype is unique, passaging experiments were repeated with a UL31 deletion mutant. After 60 passages, the resulting PrV-\u0394UL31Pass replicated similarly to wild-type PrV. Ultrastructural analyses confirmed escape from the nucleus via NEBD, indicating an inherent genetic disposition in herpesviruses. To identify the mutated viral genes responsible for this phenotype, the genome of PrV-\u0394UL34Pass was sequenced and compared to the genomes of parental PrV-Ka and PrV-\u0394UL34. Targeted sequencing of PrV-\u0394UL31Pass disclosed congruent mutations comprising genes encoding tegument proteins (pUL49, pUL46, pUL21, pUS2), envelope proteins (gI, pUS9), and protease pUL26. To investigate involvement of cellular pathways, different inhibitors of cellular kinases were tested. While induction of apoptosis or inhibition of caspases had no specific effect on the passaged mutants, roscovitine, a cyclin-dependent kinase inhibitor, and U0126, an inhibitor of MEK1\/2, specifically impaired replication of the passaged mutants, indicating involvement of mitosis-related processes in herpesvirus-induced NEBD.<\/jats:p>","DOI":"10.1128\/jvi.00068-12","type":"journal-article","created":{"date-parts":[[2012,4,6]],"date-time":"2012-04-06T01:00:57Z","timestamp":1333674057000},"page":"6512-6521","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":44,"title":["Analysis of Viral and Cellular Factors Influencing Herpesvirus-Induced Nuclear Envelope Breakdown"],"prefix":"10.1128","volume":"86","author":[{"given":"Katharina S.","family":"Grimm","sequence":"first","affiliation":[{"name":"Institutes of Molecular Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara G.","family":"Klupp","sequence":"additional","affiliation":[{"name":"Institutes of Molecular Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Granzow","sequence":"additional","affiliation":[{"name":"Infectology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik M.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institutes of Molecular Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Institutes of Molecular Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Mettenleiter","sequence":"additional","affiliation":[{"name":"Institutes of Molecular Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4613-2383-9_3"},{"key":"e_1_3_2_3_2","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1002\/jcb.22477","article-title":"Extracellular-regulated kinase-mitogen-activated protein kinase cascade: unsolved issues","volume":"109","author":"Bodart JFL","year":"2010","unstructured":"BodartJFL. 2010. 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