Gene Expression of Papillomaviruses.
Mina Kalantari and Hans-Ulrich Bernard
from: Papillomavirus Research: From Natural History To Vaccines and Beyond (Edited by: M. Saveria Campo). Caister Academic Press, U.K. (2006)
All papillomaviruses (PVs) contain a 400-850 bp long noncoding region (referred to as long control region, LCR, or upstream regulatory region, URR), which is positioned between the L1 and E6 genes and contains most of the elements that regulate transcription. All PVs have in common that transcription of early and late genes occurs uni-directionally from one or several promoters located in the LCR or in the E6 and E7 genes. All transcripts undergo differential splicing, which processes the seven to nine genes of PVs to numerous different polycistronic mRNAs. The detailed mechanisms that regulate transcription vary significantly between remotely related PVs such as animal PVs, cutaneous human PVs (HPVs), and alpha (or "genital") PVs. This review concentrates on the latter group, which has been most thoroughly studied. All alpha PVs contain an E6 promoter that is activated by a TATA box and an Sp1 binding site and down-regulated through a feedback loop executed by HPV E2 proteins. An enhancer, centered about 400 bp upstream of the E6 promoter, activates transcription specifically in epithelial cells by the synergism between numerous different transcription factors, with AP-1 playing a major role in the epithelial specificity. The specificity of this enhancer is probably the sole source of the epitheliotropism of HPVs. A silencer, modulated by YY1 and CDP, is positioned between the enhancer and the promoter, and appears to be important to couple HPV transcription with the differentiation of stratified epithelia. The HPV DNA exists in the nucleus of infected cells in the form of chromatin, i.e. wrapped around nucleosomes. The nucleosomal structure determines the accessibility of cis-responsive elements and is modulated by histone acetylation and deacetylation that is mediated by some of the factors that bind the enhancer and the silencer, and by DNA methylation. Yet other mechanisms influencing HPV gene expression include mRNA stability and altered transcription after recombination between HPV genomes and host DNA. The interactions between these different regulatory levels are likely a major source that determines the alternative outcomes of HPV infections, namely persistence in a subclinical state or progression to benign and malignant lesions read more ...