Hj. List et al., METHYLATION SENSITIVITY OF THE ENHANCER FROM THE HUMAN PAPILLOMAVIRUSTYPE-16, The Journal of biological chemistry, 269(16), 1994, pp. 11902-11911
The human papillomavirus type 16 is associated with anogenital cancer.
Transcription of the viral transforming genes E6 and E7 is under the
control of an epithelial cell type-specific enhancer. In the enhancer
core, we have identified a regulatory element that is recognized by a
novel nuclear factor named MSPF (methylation-sensitive papillomavirus
transcription factor). Mutating the MSPF binding site strongly affects
the enhancer activity. The MSPF recognition sequence 5'-ATGCGNNNNCGCC
T-3' contains two CpG dinucleotides, potential targets for B cytidine
methylation. DNA recognition by MSPF is strictly methylation-sensitive
, since introduction of 5-methylcytidine into either CpG abolishes com
plex formation. Moreover, CpG methylation of the MSPF binding site sup
presses the activity of the enhancer and of the MSPF enhanson subfragm
ent in vivo. In the cervical carcinoma cell line CaSki, which has inte
grated multiple transcriptionally inactive human papilloma virus 16 ge
nomes, a few of the viral genomes are methylated at the MSPF binding s
ite. These findings suggest that viral transcription can be suppressed
by methylation of the regulatory region, an event that prevents bindi
ng of the cellular transcription factor MSPF.