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Human adenoviruses have evolved sophisticated mechanisms that drive the infected cells into S-phase to ensure that viral genomes are efficiently replicated. We have identified an E1A mutant, E1A289R<jats:italic>dl<\/jats:italic>2\u201311\/YC, that disrupts the canonical means of S-phase induction by E1A. Specifically, this mutant abrogates binding of E1A to the E2F\/DP complex as well as to the retinoblastoma protein. Yet, we show that this mutant can still effectively drive the infected cell into S-phase. We explore potential mechanisms of how this occurs via cellular transcriptomic analysis 16 hours after infection. We show that this mutant induces many cell-cycle specific genes to drive S-phase. Interestingly, MYC mRNA is significantly upregulated by this mutant as compared to other viruses investigated. This MYC upregulation, together with normal expression of E4orf6\/7 in this mutant, may contribute to efficient S-phase induction. We also demonstrate that this mutant is unable to effectively suppress innate immune response to infection, likely due to loss of p300\/CBP binding caused by deletion of E1A residues 2 to 11.<\/jats:p>","DOI":"10.1371\/journal.pone.0323494","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T18:09:22Z","timestamp":1748369362000},"page":"e0323494","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cellular transcriptomics of arrested normal lung fibroblasts IMR-90 infected with Human Adenovirus 5 E1A mutants"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3442-6723","authenticated-orcid":true,"given":"Rafe","family":"Helwer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0099-0422","authenticated-orcid":true,"given":"Peter","family":"Pelka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"pone.0323494.ref001","volume-title":"Fields virology","author":"AJ. 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