The Wickramasinghe laboratory uses cutting-edge cell biology, molecular biology and genetic approaches to understand a critical step in gene expression, messenger RNA export. Nuclear export of mRNA to the cytoplasm is required for gene expression and is deregulated in cancer.
Our ultimate goal is to use these fundamental biological insights to develop novel first-in-class inhibitors to treat cancer.
Mechanisms of regulating gene expression via selective mRNA transport
A critical step in the gene expression pathway that is altered in cancer is nuclear export of mRNA. We have demonstrated that mRNA export is not constitutive, but highly selective and can regulate distinct biological processes through poorly understood mechanisms. This project aims to dissect the molecular mechanisms of regulating gene expression via selective mRNA transport. This will establish selective mRNA export as a novel area of research in cancer biology.
Exploiting messenger RNA export as a novel therapeutic strategy to treat cancer
Novel therapies for cancers represent an area of unmet clinical need. We have identified a new biological pathway implicated in cancer, namely selective mRNA export. Compounds inhibiting other steps of the gene expression pathway are promising therapeutic candidates for cancer, yet mRNA export inhibitors do not exist. We propose to develop first-in-class inhibitors of mRNA export that selectively target transcriptionally addicted cancers with dysregulated RNA processing.
GJ Goodall* and VO Wickramasinghe*. (2020) RNA in cancer. Nature Reviews Cancer 2020 Oct 20. doi: 10.1038/s41568-020-00306-0.
S Chappaz, CW Law, MR Dowling, KT Carey, RM Lane, LH Ngo, VO Wickramasinghe, GK Smyth, ME Ritchie, BT Kile. (2020) Germline heterozygous mutations in Nxf1 perturb RNA metabolism and trigger thrombocytopenia and lymphopenia in mice. Blood Advances 4 (7): 1270-1283.
M Briese, N Haberman, CR Sibley, R Faraway, AS Elser, AM Chakrabarti, Z Wang, J Konig, D Perera, VO Wickramasinghe, AR Venkitaraman, NM Luscombe, L Saieva, L Pellizzoni, CWJ Smith, T Curk and J Ule. (2019) A systems view of spliceosomal assembly and branchpoints with iCLIP. Nature Structural Molecular Biology doi: 10.1038/s41594-019-0300-4
KT Carey and VO Wickramasinghe*. (2018) Regulatory potential of the RNA processing machinery: Implications for human disease. Trends in Genetics 34 (4): 279-290.
T Williams, LH Ngo and VO Wickramasinghe*. (2017) Nuclear export of RNA: Different sizes, shapes and functions. Seminars in Cell and Developmental Biology (17) 30059-9
Y Liu, M Gonzàlez-Porta, S Santos, A Brazma, JC Marioni, R Aebersold*, AR Venkitaraman* and VO Wickramasinghe* (2017). Impact of alternative splicing on the human proteome. Cell Reports. 20: 1229-1241.
Wickramasinghe VO* and Venkitaraman AR* (2016). RNA processing and genome stability: cause and consequence. Molecular Cell. 61(4):496-505.
Wickramasinghe VO, Gonzàlez-Porta M, Perera D, Bartolozzi AR, Sibley CR, Hallegger M, Ule J, Marioni JC, Venkitaraman AR (2015). Regulation of constitutive and alternative mRNA splicing across the human transcriptome by PRPF8 is determined by 5’ splice site strength. Genome Biology. 16(1):201.
Wickramasinghe VO* and Laskey RA* (2015). Control of mammalian gene expression by selective mRNA export. Nature Reviews Molecular Cell Biology. 16(7):431-42.
Wickramasinghe VO*, Andrews R, Ellis P, Langford C, Gurdon JB, Stewart M, Venkitaraman AR, Laskey RA. (2014). Selective nuclear export of specific classes of mRNA from mammalian nuclei is promoted by GANP. Nucleic Acids Research. 42(8):5059-71.
Wickramasinghe VO, Savill JM, Chavali S, Jonsdottir AB, Rajendra E, Grüner T, Laskey RA, Babu MM, Venkitaraman AR (2013). Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. Molecular Cell. 51(6):737-50.
Jani D, Lutz S, Hurt E, Laskey RA, Stewart M, Wickramasinghe VO* (2012). Functional and structural characterization of the mammalian TREX-2 complex that links transcription with nuclear messenger RNA export. Nucleic Acids Research. 40(10):4562-73.
Wickramasinghe VO*, McMurtrie PIA, Mills AD, Takei Y, Penrhyn-Lowe S, Amagase Y, Main S, Marr J, Stewart M, Laskey RA (2010). mRNA export from mammalian cell nuclei is dependent on GANP. Current Biology. 20(1):25-31.