Hepatitis B virus (HBV) is a major cause for cirrhosis and hepatocellular carcinoma. Since efficient, curative HBV treatment is lacking, there is an urgent need to further explore its lifecycle in order to identify central mechanisms that can be targeted by new therapies. The virus transfers its genome into the nucleus of the infected cell as a nicked double-stranded DNA. After the nick has been sealed, the viral genome is maintained as ~3.2 kb covalently closed circular DNA (cccDNA). This is transcribed into several transcripts, including the pre-genomic RNA which is subsequently reverse-transcribed into viral DNA. Viral transcription depends on the association of the HBV X (HBx) protein to the cellular DDB1 (Damage DNA Binding 1) protein, which is a subunit of the DDB1-CUL4-RING (DDB1-CRL4) ubiquitin E3-ligase. Interestingly, HBx does not only control viral transcription, but also expression of non-viral reporter genes present on episomal DNA. However, when reporter genes are integrated into chromosomal DNA, their expression are unaffected by HBx. New results now reveal that HBx controls viral transcription through DBB1-CRL4-dependent degradation of the Structural Maintenance of Chromosome (SMC) Smc5/6 complex (Smc5/6).

The student will be involved in a project that focuses on the Smc5/6 – transcription interplay, and investigates the possibility to study Hepatitis B virus (HVB) function and inhibition in versatile yeast model systems. The specific aims are to:
1.Establish an vivo screening system for analysis of HBV inhibition and function
2. Unravel the molecular details of Smc5/6-dependet transcriptional inhibition

Interested students will contribute to the second aim, and work in a well-defined sub-project. This will allow her/him to increase his/her knowledge in genetics, molecular biology and the use of yeast model organisms, as well as in HBV control and fundamental aspects of transcription regulation.