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Molecular Functions of Multi-SUMO-Binding Protein Complexes
[Thesis]. Manchester, UK: The University of Manchester; 2019.
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Abstract
Gene expression is regulated in many ways, one of which is SUMOylation of transcription factors and associated complexes. This covalent modification by small ubiquitin-like modifier (SUMO) enables recruitment of reader proteins through their SUMO-interacting motifs (SIMs), and multiple SIM-containing proteins prefer binding to multiple SUMOs, presented either in poly-SUMO chains or multiple SUMOs presented together by a multi-SUMOylated target. A protein complex has emerged as multi-SUMO binding, the five friends of methylated CHTOP (5FMC), previously described as being involved in transcription regulation, possibly through deSUMOylation and activation of transcription factors. The complex contains 5 core members â€Â“ PELP1, TEX10, WDR18, LAS1L and SENP3. In this study we aimed to find reader proteins that specifically bind to multi-SUMOylated targets, and further characterise them. We focused on the multi-SUMO recruitment of the 5FMC complex, its recruitment to chromatin, and the effects of the 5FMC complex on SUMO binding to chromatin and impact on gene expression. We have confirmed that the 5FMC complex is recruited preferentially to multiple SUMOs, and that when complex members are missing, no such recruitment occurs in-vitro. However, individual complex member knockdowns did not uncover the effects of the whole complex on gene expression, and implied instead that active sub-complexes exist, possibly joining together as needed to assemble the 5FMC complex. We found no effect on SUMO binding to chromatin following SENP3 knockdown, possibly indicating high redundancy of the SUMO protease, but also implying the possibility that the 5FMC complex is not necessarily a deSUMOylating complex in that context. We further looked at the dynamics of SUMO recruitment to chromatin, and found complex dynamic binding patterns following EGF induction, further emphasising the importance of SUMO binding in gene regulation.