Rajagopalan, DeepaPandey, Amit KumarXiuzhen, Magdalene ClaireLee, Kwok KinHora, ShainanZhang, YanzhouChua, Boon HaowKwok, Hui SiBhatia, Shreshtha SaileshDeng, Lih WenTenen, DanielKappei, DennisJha, Sudhakar2017-12-062017Rajagopalan, D., A. K. Pandey, M. C. Xiuzhen, K. K. Lee, S. Hora, Y. Zhang, B. H. Chua, et al. 2017. “TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter.” PLoS Pathogens 13 (10): e1006681. doi:10.1371/journal.ppat.1006681. http://dx.doi.org/10.1371/journal.ppat.1006681.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493197HIV1-TAT interactive protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. It plays a vital role in virus-induced cancers where TIP60 down-regulates the expression of human papillomavirus (HPV) oncoprotein E6 which in turn destabilizes TIP60. This intrigued us to identify the role of TIP60, in the context of a viral infection, where it is targeted by oncoproteins. Through an array of molecular biology techniques such as Chromatin immunoprecipitation, expression analysis and mass spectrometry, we establish the hitherto unknown role of TIP60 in repressing the expression of the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1 at K639, thus inhibiting Sp1 binding to the TERT promoter. We identified that TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression through Sp1 acetylation. In summary, our study has identified a novel substrate for TIP60 catalytic activity and a unique repressive mechanism acting at the TERT promoter in virus-induced malignancies.en-USBiology and life sciencesGeneticsGene expressionGene regulationSmall interfering RNAsBiochemistryNucleic acidsRNANon-coding RNAPhysical SciencesChemistryChemical ReactionsAcetylationBiology and Life SciencesProteinsPost-Translational ModificationMolecular BiologyMolecular Biology TechniquesTransfectionBiological culturesCell linesHeLa cellsCell culturesCultured tumor cellsEnzymologyEnzymesOxidoreductasesLuciferaseOrganismsVirusesDNA virusesPapillomavirusesHuman PapillomavirusMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensMedicine and Health SciencesPathology and Laboratory MedicinePathogensUrologyGenitourinary InfectionsHuman Papillomavirus InfectionInfectious DiseasesSexually Transmitted DiseasesViral DiseasesMolecular Biology Assays and Analysis TechniquesGene Expression and Vector TechniquesHyperexpression TechniquesJournal Article2017-12-0610.1371/journal.ppat.1006681