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.