Project Description

TP16: Role of DNA repair, SUMOylation and nuclear bodies in the formation of the hepatitis B virus cccDNA persistence reservoir

Despite the availability of an effective vaccine, around 240 million people worldwide are chronically infected with hepatitis B virus (HBV). At present there is no cure since current therapies do not target the persistence reservoir of the virus, which is the episomal covalently closed circular DNA (cccDNA). In this project we will therefore investigate the impact of (i) promyelocytic leukemia protein (PML) nuclear bodies (PML-NBs), (ii) the DNA repair machinery and (iii) posttranslational modifications on cccDNA establishment and maintenance to unravel cellular and viral strategies involved in the establishment and maintenance of HBV cccDNA reservoirs in the nucleus.
Lampl S, Janas MK, Donakonda S, Brugger M, Lohr K, Schneider A, Manske K, Sperl LE, Kläger S, Küster B, Wettmarshausen J, Müller C, Laschinger M, Hartmann D, Hüser N, Perocchi F, Schmitt-Kopplin P, Hagn F, Zender L, Hornung V, Borner C, Pichlmair A, Kashkar H, Klingenspor M, Prinz M, Schreiner S, Conrad M, Jost PJ, Zischka H, Steiger K, Krönke M, Zehn D, Protzer U, Heikenwälder M, Knolle PA, Wohlleber D. Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes. J Hepatol. 2020 Jun 26:S0168-8278(20)30398-6. doi: 10.1016/j.jhep.2020.06.026. (TP05, TP06, TP10, TP11, TP13, TP16, TP18)

Stubbe M, Mai J, Paulus C, Stubbe H.C, Berscheminski J, Karimi M, Hofmann S, Weber E, Hadian K, Hay R, Groitl P, Nevels M, Dobner T, Schreiner S 2020. Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers. mBio, 11(2), e00049-20. (TP16)

A. Hofmann S, Mai J, Masser S, Groitl P, Hermann A, Brack-Werner R, Sternsdorf T, Schreiner S. 2019. ATO (Arsenic Trioxide) effects on PML nuclear bodies reveals antiviral intervention capacity. Advanced Science, manuscript accepted
B. Wing P, Davenne, Wettengel J, Lai A, Chakraborty A, D’Arienzo V, Kramer C, Ko C, Harris J, Schreiner S, Higgs M, Parish J, Protzer U, Balfe P, Rehwinkel J, McKeating JA. 2019. A dual role for SAMHD1 in HBV cccDNA synthesis and RT-dependent particle genesis. Life Sci Alliance. 2(2):pii: e201900355
C. Müncheberg S, Hay TR, Ip HW., Meyer T, Weiß C, Brenke J, Masser S, Hadian K, Dobner T, Schreiner S. 2018. E1B-55K mediated regulation of RNF4 STUbL promotes HAdV gene expression. J Virol. 92(13): pii: e00164-18
D. Freudenberger N, Hay RT, Groitl P, Dobner T, Schreiner S. 2018. HAdV pV core protein is targeted by the host SUMOylation machinery to pursue essential viral functions. J Virol. 92(4): pii: e01451-17
E. Schreiner S and Nassal M. 2017. A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation-and Beyond? Viruses. 9(5). Perspective Review.
F. Wimmer P, Berscheminski J, Blanchette P, Groitl P, Branton PE, Hay RT, Dobner T, Schreiner S. 2016. PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor suppressor p53. Oncogene. 35(1):69-82.
G. Berscheminski J, Brun J, Speiseder T, Wimmer P, Ip WH, Terzic M, Dobner T, Schreiner S. 2015. Sp100A is a tumor suppressor that activates p53-dependent transcription and countercats E1A/E1B-55K-mediated transformation. Oncogene. 35(24):3178-89.
H. Berscheminski J, Wimmer P, Brun J, Ip WH, Horlacher T, Groitl P, Jaffray E, Hay RT, Dobner T, Schreiner S. 2014. Sp100 isoform-specific regulation of human Adenovirus type 5 (Ad5) gene expression. J Virol. 88(11):6076-92.
I. Schreiner S, Kinkley S, Bürck C, Mund A, Wimmer P, Schubert T, Groitl P, Dobner T. 2013. SPOC1-mediated antiviral host cell responses antagonized early in Human Adenovirus type 5 infection. PLoS Pathog. 9(11):e1003775.
J. Schreiner S, Bürck C, Glass M, Groitl P, Wimmer P, Kinkley S, Mund A, Everett RD and Dobner T. 2013. Control of human adenovirus type 5 gene expression by cellular Daxx/ATRX chromatin-associated complexes. Nucleic Acids Res. 41(6):3532-50.
*co-first/co-last authorship