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November 6th 2017
A new article from the Lamond group, published in eLife, reports the identification of the plant biflavone, hinokiflavone, as a pre-mRNA splicing modulator (Pawellek et al., 2017). In collaboration with Ron Hay’s group in GRE and the group of Richard Hartley, (University of Glasgow), they show that both natural and synthetic hinokiflavone inhibits splicing in vitro by blocking spliceosome assembly, specifically preventing progression from the spliceosome complex A to complex B. Further, they find that hinokiflavone binds to and inhibits the SUMO protease, SENP1, in vitro and causes an increase in the levels of SUMO2-modified proteins in cellulo. Using an unbiased, SILAC MS-based proteomics assay, the major protein targets that are hyper-SUMOylated in cells treated with hinokiflavone were shown to include six proteins that are all components of the U2 snRNP spliceosome subunit that is required for A complex formation. This study identifies hinokiflavone as a potential novel cancer therapeutic and points to a role for protein SUMOylation in regulating spliceosome formation and alternative splicing.
A collaborative study, carried out by the Lamond group and the Watt laboratory at King’s College London, entitled “A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis”, has been accepted for publication in eLife (Mishra et al., eLife 2017). Described by the editor as a 'tour de force' analysis of phosphatase function in human skin stem cells during differentiation, this study integrates transcriptomic and proteomic data to identify the role of protein phosphatases in regulation of epidermal differentiation. This identifies five protein phosphatases, i.e., DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA, which promote differentiation by negatively regulating ERK & MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression was shown to antagonise commitment. These protein phosphatases form an auto-regulatory dynamic network, including transient positive and negative interactions, that maintains epidermal homeostasis by controlling the onset and duration of commitment to differentiation.