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  Role of m6A methylation in virus infection


   Faculty of Biological Sciences

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Prof Ade Whitehouse Dr A.K Tuplin  No more applications being accepted  Competition Funded PhD Project (European/UK Students Only)

About the Project

RNA can be chemically modified and it’s now emerging that the modification status of an RNA can affect its fate and function. The most common mRNA modification, m6A methylation, functions by recruiting so-called effector m6A reader proteins to modified RNAs. Once bound these m6A reader proteins determine RNA processing events. Not surprisingly, viruses manipulate the host cell RNA modification machinery to enhance virus replication. We have recently shown that KSHV-encoded RNAs are heavily m6A modified and that the modification of host cell RNAs is drastically altered during infection (Baquero et al., (2019) eLife, 8:e47261). This project now aims to determine how and why KSHV manipulates the host’s RNA modification machinery. We will address the key question of why the m6A modification status of host cell RNAs are altered and how this enhances KSHV replication. This may provide new avenues to antiviral strategies.
This project uses an interdisciplinary approach, combining virology and cell biology, coupled with transcriptomic analysis and bioinformatics. You will be provided training in a wide range of confocal imaging approaches and molecular/virological techniques, in addition to bioinformatic approaches to analyse transcriptome/CLIP-seq data and quantitative skills to analyse differential expression patterns.

More information on the Whitehouse lab can be found at : http://www.fbs.leeds.ac.uk/staff/Whitehouse_A/


Funding Notes

White Rose BBSRC Doctoral Training Partnership in Mechanistic Biology
4 year fully-funded programme of integrated research and skills training, starting Oct 2020:
• Research Council Stipend
• UK/EU Tuition Fees
• Conference and research funding

Requirements:
At least a 2:1 honours degree or equivalent. We welcome students with backgrounds in biological, chemical or physical sciences, or mathematical backgrounds with an interest in biological questions.

EU candidates require 3 years of UK residency to receive full studentship

Not all projects will be funded; the DTP will appoint a limited number of candidates via a competitive process.

https://phd.leeds.ac.uk/funding/81-white-rose-bbsrc-doctoral-training-partnership-in-mechanistic-biology

References



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Project supervisors

Career overview

Professor Ade Whitehouse obtained a BSc in Microbiology from the University of Sheffield in 1991 and a D.Phil in Molecular Virology from the University of Oxford in 1994. Following postdoctoral work at the Molecular Medicine Unit, St James’s Hospital in Leeds, he was awarded a Medical Research Council Non-clinical Fellowship in 1998. Professor Whitehouse joined the School of Molecular & Cellular Biology at the University of Leeds as a Lecturer in 2002, was appointed to Reader in 2005, and became a Professor of Molecular Virology in 2010. His research focuses on the relationship between viruses and cancer, particularly how viruses cause cancer and the development of novel antiviral strategies to prevent infection and tumourigenesis. He studies the molecular biology of Kaposi''s sarcoma associated herpesvirus (KSHV) and Merkel cell polyomavirus (MCPyV), both of which are linked to human cancers.


Research interests

Professor Whitehouse''s research focuses on the intersection of virology and cancer, specifically how viruses contribute to oncogenesis. Their work aims to understand the mechanisms by which viruses cause cancer and to develop innovative antiviral strategies to prevent viral infections and tumourigenesis. The Whitehouse laboratory studies two recently discovered human tumour viruses: Kaposi''s sarcoma-associated herpesvirus (KSHV) and Merkel cell polyomavirus (MCPyV). KSHV is linked to various lymphoproliferative disorders, including Kaposi''s sarcoma, which has become an epidemic disease in sub-Saharan Africa due to widespread HIV infection. The research investigates the molecular mechanisms regulating lytic gene expression to enhance understanding of KSHV pathogenesis. MCPyV is associated with Merkel cell carcinoma, a highly aggressive skin cancer. Given its recent discovery, the laboratory is exploring the role of MCPyV-encoded proteins in the transformation and immortalisation of human cells. Current projects include identifying essential virus-host cell interactions necessary for virus replication or transformation, employing transcriptomic and quantitative proteomic techniques. These interactions are verified through biochemical and confocal imaging methods, focusing on RNA processing and translation control during viral infection. Additionally, the research involves structural-based rational drug design to create small molecules that inhibit oncogenic viruses, particularly targeting KSHV and MCPyV. Professor Whitehouse''s ongoing research projects encompass various aspects of virus-host interactions, KSHV-induced translation, live cell imaging of pathogenic viruses, and the development of novel antiviral approaches.

View Professor Ade Whitehouse's profile 
Career overview

Dr Andrew Tuplin holds a BSc and a PhD from the University of Edinburgh. He has held positions as a research fellow at the Centre for Ecology and Hydrology in Oxford and at the University of Warwick, where he progressed to the role of senior research fellow. Currently, Dr Tuplin serves as an Associate Professor in the School of Molecular and Cellular Biology at the University of Leeds. His research primarily focuses on molecular virology, particularly the control of replication and translation in positive-strand RNA viruses, with a specific interest in mosquito-transmitted arboviruses such as chikungunya virus and dengue virus. Dr Tuplin employs a variety of advanced molecular virology and cell biology techniques in his research, which is funded by the MRC, BBSRC, and The Royal Society. He also leads a research group and is the SMCB Admissions Tutor, as well as a Program Leader for Biological Sciences and Bioengineering.


Research interests

Dr Tuplin''s research focuses on the control of replication and translation in positive-strand RNA viruses, particularly mosquito-transmitted arboviruses such as chikungunya virus and dengue virus. The research investigates how RNA viruses manage genome replication and translation through dynamic interactions involving structured RNA, host-cell/viral proteins, and various types of non-coding RNA (ncRNA), including siRNA, lncRNA, and circRNA. This work aims to identify potential novel therapeutic targets. Dr Tuplin employs a range of advanced molecular virology and cell biology techniques, including genomics, proteomics, in-cell RNA SHAPE-MaP, and CryoEM. The research is funded by the MRC, BBSRC, and The Royal Society. Current projects include exploring the regulatory mechanisms of chikungunya virus and developing live cell imaging capabilities for studying pathogenic viruses. Additionally, the research encompasses the structural and mechanistic analysis of host cell and viral ncRNA during virus replication and RNA modification processes.

View Dr Andrew Tuplin's profile