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Investigation of the effects of SUMO modification on two critical proteins : a pathogenic NEK1 mutant that drives ALS pathogenesis and the CRISPR-associated CAS9 protein

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dc.contributor Graduate Program in Molecular Biology and Genetics.
dc.contributor.advisor Şahin, Umut.
dc.contributor.author Ergünay, Tunahan.
dc.date.accessioned 2023-10-15T17:02:23Z
dc.date.available 2023-10-15T17:02:23Z
dc.date.issued 2022
dc.identifier.other BIO 2022 E74
dc.identifier.uri http://digitalarchive.boun.edu.tr/handle/123456789/19936
dc.description.abstract Small Ubiquitin-like modifier (SUMO) is an essential eukaryotic post-translational modification. SUMO isoforms attach to specific lysine residues on target substrates to modi-fy their function, activity, solubility and stability. Dysregulation of sumoylation is associated with various pathological conditions ranging from cancer to neurodegeneration. In this study, we focused on a mutant form of NEK1 protein, called truncated NEK1 (or tNEK1), which was recently linked to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Previous studies from our lab had established that tNEK1 was prone to aggregation and associated with PML nuclear bodies (NBs). Here, we showed that PML also facilitates tNEK1 sumoylation and ubiquitylation. Furthermore, pharmaceutical agents that induce PML NB biogenesis, such as interferon-alpha (IFN), promote tNEK1 hypersumoylation in a PML-dependent manner. These findings have important implications for the management of tNEK1-linked ALS in the clinic, as IFN may promote the hypersumoylation, degradation, and clearance of this toxic protein in vivo, in a PML-dependent manner. In addition, our lab has created a transgenic mice model that expressed tNEK1 to study the effect of this mutation in vivo. In this study, we have performed motor neuron function assays (specifically, foot-print and walking assays). Our results indicate that tNEK1-expressing mice display a walk-ing disorder, implying that tNEK1 expression in vivo may lead to ALS pathogenesis. Finally, we have also conducted studies on the CRISPR-associated Cas9 protein that we have recently discovered to be a sumoylation target. We have identified the major SUMO conjugation site on this protein and showed that sumoylation impacted on both the stability and DNA-binding ability of this important protein.
dc.publisher Thesis (M.S.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2022.
dc.subject.lcsh Amyotrophic lateral sclerosis.
dc.title Investigation of the effects of SUMO modification on two critical proteins : a pathogenic NEK1 mutant that drives ALS pathogenesis and the CRISPR-associated CAS9 protein
dc.format.pages xvi, 82 leaves


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