Sebastiaan gained his PhD from Erasmus Medical Centre (The Netherlands), where he studied the biochemistry of DNA repair disorders. He then did his postdoctoral training in the Cancer Research London Research Institute at Clare Hall laboratories, which was supported by an EMBO Long Term Fellowship. After taking up a position at the University Medical Centre Utrecht (The Netherlands), he joined the School of Pharmacy in 2007, where he established an independent research programme concentrating on eukaryotic gene regulation.
A central theme in Sebastiaan's research is to understand the post-transcriptional control of mRNA levels and the relevance of these processes for normal physiology and disease. Research in his… read more
FARAJI F, HU Y, YANG HH, LEE MP, WINKLER GS, HAFNER M and HUNTER KW, 2016. Post-transcriptional Control of Tumor Cell Autonomous Metastatic Potential by CCR4-NOT Deadenylase CNOT7. PLoS genetics. 12(1), e1005820 NAIM HAGE, TINA HOWARD, CHRIS PHILLIPS, CLAIRE BRASSINGTON, ROSS OVERMAN, JUDIT DEBRECZENI, PAUL GELLERT, SNOW STOLNIK, G SEBASTIAAN WINKLER and F FALCONE, 2015. Structural basis of Lewisb antigen binding by the Helicobacter pylori adhesin BabA Science Advances. 1(e1500315),
LOCZENSKI ROSE, VANESSA, SHUBBER, SAIF, SAJEESH, S, SPAIN, SEBASTIAN G, PURI, SANYOGITTA, ALLEN, STEPHANIE, LEE, DONG-KI, WINKLER, G SEBASTIAAN and MANTOVANI, GIUSEPPE, 2015. Phosphonium Polymethacrylates for Short Interfering RNA Delivery: Effect of Polymer and RNA Structural Parameters on Polyplex Assembly and Gene Knockdown. Biomacromolecules. 16(11), 3480-90
Pharmacy School Building, East Drive, University Park, Nottingham, NG7 2RD
A central theme in Sebastiaan's research is to understand the post-transcriptional control of mRNA levels and the relevance of these processes for normal physiology and disease. Research in his laboratory was sponsored by the BBSRC, AICR, and MRC.
Degradation of cytoplasmic mRNA: the role of deadenylase enzymes
The shortening of the poly(A) tail of cytoplasmic mRNA (deadenylation) is a pivotal step in the regulation of gene expression in eukaryotic cells. An important enzyme complex involved in poly(A) shortening is the Ccr4-Not deadenylase. In addition to at least six non-catalytic subunits, it contains two distinct subunits with ribonuclease activity: a Caf1 and a Ccr4 component. In vertebrate cells, the complexity of the complex is further increased by the presence of paralogues of the Caf1 subunit (encoded by either CNOT7 or CNOT8) and the occurrence of two Ccr4 paralogues (encoded by CNOT6 or CNOT6L). Using genome-wide expression profiling, we investigated whether the deadenylase subunits of the Ccr4-Not complex cooperate, or whether these proteins have unique roles. More recently, we have also started a biochemical approach to understand the mechanism of deadenylation in more detail (Aslam et al. MBC 20:3840-50, 2009; Mittal et al. MBC 22:748-58, 2011; reviewed in Wahle & Winkler, BBA 1829: 561-70, 2013; Maryati et al. Biochem J. 469:169-176, 2015; Cano et al. Nature Comm 6:8670, 2015; Faraji et al. PLoS Genet 12:e1005820, 2016; Pavanello et al. Biochem J 475:3437-50, 2018).
BTG/TOB proteins and cancer
The human BTG/TOB protein family comprises six members (BTG1, BTG2/PC3/Tis21, BTG3/Ana, BTG4/PC3B, TOB1/Tob, and TOB2) that are characterised by a conserved BTG domain. This domain mediates interactions with the highly similar Caf1 subunits of the Ccr4-Not deadenylase complex. BTG/TOB proteins have anti-proliferative activity and are frequently down-regulated in various cancers. We showed that the interaction between BTG2/TOB1 and the Caf1 deadenylases is necessary for their anti-proliferative activity (Doidge et al. Plos One 7: e51331, 2012; reviewed in Winkler J Cell Physiol 222: 66-72, 2010).
Biochemistry and chemical biology of deadenylase enzymes
Novel tools, such as chemical probes, will be valuable to further understand the role of deadenylase enzymes in physiology and to evaluate this class of enzymes as potential therapeutic targets. To this end, we developed a fluorescence-based assay for deadenylase enzymes. Using in-house facilities comprising an automated system for compound management and robotic liquid handlers, we have started the identification of small-molecule inhibitors of deadenylase enzymes. The screening of more extensive compound collections in combination with the synthesis and evaluation of novel chemical entities is underway (in collaboration with Prof Peter Fischer; Maryati et al. Nucleic Acids Res 42: e30, 2014; Jadhav et al. Bioorg. Med. Chem. Lett. 25:4219-24, 2015; Airhihen et al. FEBS Open Bio 9: 717-27, 2019).
Please contact Sebastiaan directly if you are interested in a PhD project in any of these, or related, areas.