Role of HPV16 E1 in cervical carcinogenesis

Abstract

Cervical cancer is the fourth most common cancer in women worldwide. More than 90% of cases are caused by the human papillomavirus (HPV). Vaccines developed only guard against a few HPV types and do not protect people who have already been infected. HPV is a small DNA virus that infects the basal layer of the stratified epithelium of the skin and mucosa through small breaks and replicates as the cells differentiate. The mucosal types of HPV can be classified into low-risk and high-risk groups, based on their association with cancer. Among HPV types in high-risk group, HPV type 16 (HPV-16) is the most common, causing 50% of all cancer cases. HPV infection can occur as transient or persistent infections, based on the ability of immune system to clear the virus. Persistent infection is characterized by the integration of HPV genome. HPV-16 exhibits a different integration pattern, with only 50% reported to be integrated at the carcinoma stage. Replication of the HPV genome depends on protein E1, an ATP-dependent helicase. E1 is essential for the amplification of the viral episome in infected cells. Previous studies have shown that E1 does not only act as a helicase protein but is also involved in recruiting and interacting with other host proteins. E1 has also been deemed to drive host cell proliferation. Recent studies have emphasized the emerging role of HPV E1 in cervical carcinogenesis. In this review, a possible mechanism by which E1 drives cell proliferation and oncogenesis will be discussed.

Keywords: HPV; HPV16; HPV16 E1; cervical cancer; cervical carcinogenesis.

Figure 1

Structure and function of HPV E1. (A) Diagram of the HPV E1 protein domains. Three major functional domains of HPV E1, i.e., N-terminal, DNA binding domain (DBD), and the domain which construct the helicase domain: minimal oligomerization domain, ATPase domain, and C-terminal brace. (B) Schematic representation of the initiation of the HPV DNA replication associated with E1 protein. HPV E1 proteins are recruited to bind to the E1 DNA binding site at the origin by HPV E2. E1 and E2 are assemble as E1-E2-ori ternary complex. Additional of E1 proteins are recruited to assemble as E1 double-trimer and double-hexamer, respectively. Then, the ds-DNA are unwound, and the DNA replication are initiated by the recruitment of host DNA replication factors.

Figure 2

Role of HPV E1. Left panel: the well-known helicase function of HPV. Right panel: the possible roles of HPV E1 in cervical carcinogenesis include dysregulating the expression of genes involved in cell survival, E1 mutation, E1 overexpression, inducing DNA damage, viral genome maintenance, and regulating the expression of immune response genes.