Regulation of human papillomavirus gene expression by splicing and polyadenylation

ArticleinNature Reviews Microbiology 11(4) · March 2013with35 Reads
DOI: 10.1038/nrmicro2984 · Source: PubMed
Abstract
Human papillomaviruses (HPVs) are small DNA tumour viruses that are present in more than 99% of all cervical cancers. The ability of these viruses to cause disease is partly attributed to the strict coordination of viral gene expression with the differentiation stage of the infected cell. HPV gene expression is regulated temporally at the level of RNA splicing and polyadenylation, and a dysregulated gene expression programme allows some HPV types to establish long-term persistence, which is a risk factor for cancer. In this Review, we summarize the role of splicing and polyadenylation in the regulation of HPV gene expression and discuss the viral and cellular factors that control these processes.
    • "proteins [12]. In particular, viral capsid protein L1 is thought to be encoded by an E4^L1 "
    [Show abstract] [Hide abstract] ABSTRACT: Importance: Human papillomavirus replication is accomplished in concert with differentiation of the infected epithelium. Virus capsid protein expression is confined to the upper epithelial layers so as to avoid immune detection. In this study we demonstrate that the viral E2 transcription factor activates the promoter of the cellular SRSF3 RNA processing factor. SRSF3 is required for expression of the E4̂L1 mRNA and so controls expression of the HPV L1 capsid protein. Thus we reveal a new dimension of virus-host interaction crucial for production of infectious virus. SRSF proteins are known drug targets. Therefore, this study provides an excellent basis for developing strategies to regulate capsid protein production in the infected epithelium and production of new virions.
    Article · Mar 2016
    • "A strong splicing enhancer is located downstream of HPV16 3'-splice site SA3358 (Figure 1) [9,12,21,22]. This is one of the most efficiently used 3'-splice sites in the HPV16 genome despite its poor homology to a consensus 3'-splice site. "
    [Show abstract] [Hide abstract] ABSTRACT: The human papillomavirus (HPV) life cycle is strictly linked to the differentiation program of the infected mucosal epithelial cell. In the basal and lower levels of the epithelium, early genes coding for pro-mitotic proteins and viral replication factors are expressed, while terminal cell differentiation is required for activation of late gene expression and production of viral particles at the very top of the epithelium. Such productive infections are normally cleared within 18-24 months. In rare cases, the HPV infection is stuck in the early stage of the infection. Such infections may give rise to cervical lesions that can progress to cancer, primarily cancer of the uterine cervix. Since cancer progression is strictly linked to HPV gene expression, it is of interest to understand how HPV gene expression is regulated. Cis-acting HPV RNA elements and cellular RNA-binding proteins control HPV mRNA splicing and polyadenylation. These interactions are believed to play a particularly important role in the switch from early to late gene expression, thereby contributing to the pathogenesis of HPV. Indeed, it has been shown that the levels of various RNA binding proteins change in response to differentiation and in response to HPV induced cervical lesions and cancer. Here we have compiled published data on RNA binding proteins involved in the regulation of HPV gene expression.
    Full-text · Article · May 2015
    • "The prototypical papillomavirus, bovine papillomavirus 1 (BPV1), has six early promoters that each encode a different polycistronic transcript while the high-risk HPVs, such as HPV types 16 and 18, only contain one early promoter [7,8]. The polycistronic transcripts encoded from the early promoters utilize the same poly-adenylation site and are processed by cellular splicing factors [9]. Papillomavirus gene expression is strictly regulated by the differentiation status of the infected cell [10,11]. "
    [Show abstract] [Hide abstract] ABSTRACT: The cellular bromodomain protein Brd4 functions in multiple processes of the papillomavirus life cycle, including viral replication, genome maintenance, and gene transcription through its interaction with the viral protein, E2. However, the mechanisms by which E2 and Brd4 activate viral transcription are still not completely understood. In this study, we show that recruitment of positive transcription elongation factor b (P-TEFb), a functional interaction partner of Brd4 in transcription activation, is important for E2's transcription activation activity. Furthermore, chromatin immunoprecipitation (ChIP) analyses demonstrate that P-TEFb is recruited to the actual papillomavirus episomes. We also show that E2's interaction with cellular chromatin through Brd4 correlates with its papillomavirus transcription activation function since JQ1(+), a bromodomain inhibitor that efficiently dissociates E2-Brd4 complexes from chromatin, potently reduces papillomavirus transcription. Our study identifies a specific function of Brd4 in papillomavirus gene transcription and highlights the potential use of bromodomain inhibitors as a method to disrupt the human papillomavirus (HPV) life cycle.
    Full-text · Article · Aug 2014
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