Host Transcription Factors in Hepatitis B Virus RNA Synthesis

Abstract

The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA (cccDNA) that resides in the nucleus. As HBV replication requires the help of host transcription factors to replicate, focusing on host protein-HBV genome interactions may reveal insights into new drug targets against cccDNA. The structural details on such complexes, however, remain poorly defined. In this review, the current literature regarding host transcription factors' interactions with HBV cccDNA is discussed.

Keywords: covalently closed circular DNA (cccDNA); hepatitis B virus (HBV); host–viral interactions; transcription factors; viral replication.

Figure 1

Schematic of the hepatitis B virus (HBV) circular genome (dark orange parallel lines). The outer black lines represent the RNA transcripts produced, all ending in the poly-A tail. The promoter regions are denoted by the dark green rectangles preceding each of these transcripts, and the Enhancer regions I and II, (EnI and EnII) are denoted by the light green rectangles. The thicker inner arrows represent the open reading frames, encoding for the C (core), P (polymerase), S (surface), and X proteins. The encapsidation signal, ԑ, is also noted.

Figure 2

Relative positions of the binding sites of host transcription factors on the HBV genome. Promoter and enhancer sites are represented by the boxes and the directional arrow indicates the transcript produced. The arrows from one transcription factor to another represents an event in which one factor influences the binding activity of another. The two An sites represent the polyadenylation sites in the linearized genome schematic. Transcription factor activity has been indicated in which red represents inhibition of HBV transcription and black indicates activation of transcription. The lists of transcription factors are positioned to represent where they bind to the genome where they are generally positioned to 5′ or 3′ of the promoter/enhancer region (not to scale). Asterisks indicate that the specific positioning of the transcription factor is not yet known.

Figure 3

An overview of high-resolution structures of transcription factors. (A) An overlay of high-resolution structures of three zinc finger domains of Sp1 [53]. (B) A structure of COUP-TF zinc finger domain [pdb: 2EBL]. (C,D) High-resolution structures of HNF1α [201] and HNF4α [202] bound to the major groove of DNA. In both cases, cccDNA DNA sequences (5′-GTTAATNATTAAC-3′ recognized by HNF1α and 5′-CAGAGGNCAAAGTCCA-3′ by HNF4α) were used to calculate 3 dimensional structures employing 3D-DART web server [203]. (E) High-resolution structure of mouse HNF-6α DNA-binding domain bound, which is identical to human HNF-6α DNA-binding, with transthyretin (TTR) promoter [204]. (F) Dimeric structure of homeodomain 2 of ZHX2 protein [205].