title: The HPV E6 oncoprotein targets histone methyltransferases for modulating specific gene transcription.
abstract: Expression of viral proteins causes important epigenetic changes leading to abnormal cell growth. Whether viral proteins directly target histone methyltransferases (HMTs), a key family enzyme for epigenetic regulation, and modulate their enzymatic activities remains elusive. Here we show that the E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro and in HPV-transformed HeLa cells. Furthermore, these three HMTs are required for E6 to attenuate p53 transactivation function. Mechanistically, E6 hampers CARM1- and PRMT1-catalyzed histone methylation at p53-responsive promoters, and suppresses the binding of p53 to chromatinized DNA independently of E6-mediated p53 degradation. p53 pre-methylated at lysine-372 (p53K372 mono-methylation) by SET7 protects p53 from E6-induced degradation. Consistently, E6 downregulates p53K372 mono-methylation and thus reduces p53 protein stability. As a result of the E6-mediated inhibition of HMT activity, expression of p53 downstream genes is suppressed. Together, our results not only reveal a clever approach for the virus to interfere with p53 function, but also demonstrate the modulation of HMT activity as a novel mechanism of epigenetic regulation by a viral oncoprotein.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: C-H
authors.initials: CH
authors.lastname: Hsu
authors.forename: K-L
authors.initials: KL
authors.lastname: Peng
authors.forename: H-C
authors.initials: HC
authors.lastname: Jhang
authors.forename: C-H
authors.initials: CH
authors.lastname: Lin
authors.forename: S-Y
authors.initials: SY
authors.lastname: Wu
authors.forename: C-M
authors.initials: CM
authors.lastname: Chiang
authors.forename: S-C
authors.initials: SC
authors.lastname: Lee
authors.forename: W C Y
authors.initials: WC
authors.lastname: Yu
authors.forename: L-J
authors.initials: LJ
authors.lastname: Juan
mesh_terms: D002472:Cell Transformation, Viral / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D000076983:Histone Methyltransferases; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human