The Wickramasinghe laboratory investigates the molecular basis of how messenger RNA (mRNA) is selectively processed and exported from the nucleus into the cytoplasm, and how deregulation of these processes contributes to human cancer.
Specifically, we aim to:
• Understand how selective mRNA export pathways are regulated and activated.
• Investigate the effect of alternative mRNA splicing on the human proteome.
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 is 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.
Effect of alternative mRNA splicing on the human proteome
Alternative splicing of RNA transcripts has emerged as a key mechanism for enabling biological complexity within the human genome. Alternative splicing has long been assumed to underlie the expansion of proteomic diversity. However, the extent to which this increased genomic complexity contributes to the generation of proteomic diversity is largely unknown. This fundamental biological question is of critical importance to human health, given the recent identification of perturbed RNA splicing as a causative factor in cancer. We have developed an integrative approach to ask whether dynamic perturbations in mRNA splicing patterns alter the composition of the proteome. This project will reveal the effect of alternative splicing on the proteome.
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. (*Corresponding author)
Wickramasinghe VO* and Venkitaraman AR* (2016). RNA processing and genome stability: cause and consequence. Mol Cell. 61(4):496-505. (*Corresponding author)
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 Biol. 16(1):201.
Wickramasinghe VO* and Laskey RA* (2015). Control of mammalian gene expression by selective mRNA export. Nat Rev Mol Cell Biol. 16(7):431-42. (*Corresponding author)
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 Res. 42(8):5059-71. (*Corresponding author)
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. Mol 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 Res. 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. Curr Biol. 20(1):25-31. (*Corresponding author)