[SCAN] The Pivotal Role of LANA in Kaposi Sarcoma Herpesvirus (KSHV) infection

SCAN

Title: The Pivotal Role of LANA in Kaposi Sarcoma Herpesvirus (KSHV) infection

Speaker: Colin E. McVey

Affiliation: Structural Virology Lab

Abstract:

Herpesviruses establish life-long latent infections in the cell. During latency, gammaherpesviruses, such as Kaposi's sarcoma-associated herpesvirus (KSHV), persist as multicopy, circularized genomes in the cell nucleus and express a small subset of viral genes. KSHV is one of seven currently known human cancer viruses, or oncoviruses. KSHV latency-associated nuclear antigen (LANA) is the predominant gene expressed during latent infection and causes several malignancies. 

C-terminal LANA binds KSHV terminal repeat (TR) DNA to mediate DNA replication. From our previous work on the X-ray structure of LANA (PlosPahtogens 2013) we have identified a region on the oligomer assembly interface adjacent to the DNA binding region. This region was found to exert an important role in KSHV LANA’s ability to bind DNA but also to enable it to bend and rotate. This pivot region is present in kLANA, but not the mouse homolog MHV-68 LANA, which allows greater freedom in its oligomeric assembly to enable the virus to persist in a human host (NAR 2015). We can conclude that the closely related KSHV and MHV-68 viruses have evolved differently to bind TR viral DNA.

ITQB Highlights:

How we are tied to herpes virus
Viral protein takes a piggy-back on chromosomes

Correia et al. 2013 Crystal structure of the gamma-2 herpesvirus LANA DNA Binding Domain identifies charged surface residues which impact viral latency .PLOS Pathogens e1003673

Bend it like KSHV
Herpesvirus protein promotes DNA bending required for replication
Ponnusamy et al. 2015 KSHV but not MHV-68 LANA induces a strong bend upon binding to terminal repeat viral DNA. Nucleic Acid Res. doi: 10.1093/nar/gkv987

Short CV:

Academic

• Degree in Biochemistry (Hons) 1991 The Queen's University of Belfast (QUB).
• MSc in Clinical Laboratory Medicine (1992)  Department Haematology, Royal Victoria Hospital, QUB.
• DPhil Protein Structure Group in Chemistry Department, University of York

Positions

Wellcome Post-doctoral Fellow at the Sir William Dunne School of Pathology, University of Oxford, with Professor Dale Wigley, (Dale was esponsible for the solving the structure of DNA gyrase),  to work on Vaccinia virus proteins involved in immune evasion, moved to Department of Virology, Imperial College College to continue this work with Professor Geoffrey Smith

Moved to Portugal and to ITQB in 2004 with FCT Post-dcotoral Fellowship, part of the team who solved the X-ray structure of the RNaseII-RNA complex published in Nature 2006.

FCT Ciencia 2009 awardee as an Auxiliary Investigator and lead partner of one of the three research teams awarded a Harvard Portugal Program entitled “Pathogenesis of Kaposi’s sarcoma herpesvirus LANA” --> published the structure of the DNA binding domain of LANA in PlosPathogens in 2013.

FCT IF Development Principal Investigator awarded in 2014 to contine my work on LANA's role in KSHV Latency →Recent Publication Nucleic Acids Research 2015.

Honours

• 1997 Awarded the Shell Postgraduate Chemistry Research Prize. University of York, UK.
• 2007 Medalha Municipal de Mérito - Grau Ouro, Gold medal awarded by the municipal of Oeiras
• 2008 Prémio Câmara Pestana, (Instituto Câmara Pestana and GlaxoSmithkline) award acknowledges the best scientific work in microbiology in Portugal.