2.7. SUMOs in the Regulation of Transcriptional Co-regulators RIP140 and PGC-1α and in the Development of C. elegans

Public examination of a doctoral dissertation in the field of medical biochemistry

Doctoral candidate: MSc Miia Rytinki

Time and venue: 2.7.2011 at 12 noon, Snellmania L21, Kuopio Campus

Small ubiquitin-like modifier (SUMO) proteins are small ~100 amino acids long proteins that are covalently attached to specific lysine residues on substrate proteins. Humans express four different SUMO proteins, SUMO-1, -2, -3, and -4. The SUMO conjugation (SUMOy­lation) to proteins is similar to ubiquitylation pathway, but it is catalyzed by distinct enzymes. The normal SUMOylation is important at the individual protein level to maintain protein-protein interactions, subcellular and subnuclear localization, and control stability and activity. In the big picture, SUMOylation plays a role e.g. in chromatin organization, DNA repair, and cellular stress responses.

The majority of studies of SUMOylation have been done in cultured cells. In the first section of this study the SUMOylation is evaluated in a whole multicellular organism, by constructing transgenic nematode Caenorhabditis elegans (C. elegans) strains expressing SUMO-1 or SUMO-2 in muscle cells. The disrupted balance of SUMO proteins by increased expression in muscle cells disturbed the normal develop­ment of the nematode muscles. The perturbation led to severe disabilities in reproduction, movement and survival. In addition, the expression of SUMO and ubiquitin-proteasome pathway genes was altered in the SUMO-expressing nematodes.

The second section of this study considers the function of SUMOs in the regulation of two nuclear receptor co-regulators in cultured mammalian cells. The receptor interacting protein 140 (RIP140, NRIP1) and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α, PPARGC1α) are co-regulators for many gene expression pathways in metabolism and energy homeostasis. It was found that the co-repressor RIP140 is SUMOylated at two distinct residues in separate C-terminal repression domains 3 and 4. SUMOylation increased the repressive potential and modulated the localization of the co-regulator. The co-activator PGC-1α was SUMO-modified at the N-terminal activation domain. The activation function of PGC-1α was depressed by SUMO modification due to the interaction of co-repressor RIP140. In conclusion, the dissertation describes the importance of balanced SUMOylation in normal development and new mechanisms of regulation of two important transcriptional co-regulators.

The doctoral dissertation of Master of Science Miia Rytinki, entitled Balance of SUMO in transcriptional co-regulators and nematodes will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Docent Ville Hietakangas of the University of Helsinki, and the custos will be Professor Jorma Palvimo of the University of Eastern Finland.

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Publishing year: 2011

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