Protein phosphorylation is an essential regulatory mechanism employed by many key pathways in the eukaryotic cell. This thesis explored two examples of protein phosphorylation, one in translation and one in cell cycle regulation.
TRNT1 is the RNA polymerase that adds the 3’ CCA nucleotides to all tRNA and is required for aminoacylation, tRNA quality control, and protection of the translation machinery (Aebi et al., 1990; Vörtler & Mörl, 2010; Wellner et al., 2018). Mutations in TRNT1 cause SIFD, Sideroblastic Anemia With B-Cell Immunodeficiency, Periodic Fevers, And Developmental Delay, a rare mitochondrial disease (Chakraborty et al., 2014). In addition to oxidative phosphorylation defects previously reported (Liwak-Muir et al., 2016; Sasarman et al., 2012; Wedatilake et al., 2016), I show that defects in TRNT1/Cca1 induce the eIF2α-P translation stress response to slow cytoplasmic translation but is only beneficial when mitochondrial translation is required. This data suggests that impairment of TRNT1/Cca1 function results in an imbalance of translation homeostasis and that altering the balance between mitochondrial and cytoplasmic translation may be an effective therapy for SIFD.
In another example of protein phosphorylation regulation, Cdc25-dependent dephosphorylation of Cyclin dependent kinase (Cdk1) is a universally conserved mechanism regulating mitotic entry. In budding yeast, Cdk1 is dephosphorylated when the cdc25 homologue, MIH1, is deleted, indicating an additional phosphatase functions redundantly with Mih1. I identified two phosphatases, Ptp1 and PP2ARts1, that function in conjunction with Mih1. This redundancy suggests novel mechanisms for how cells may activate pools of Cdk1 at different times and in different cellular locations.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/38010 |
| Date | 22 August 2018 |
| Creators | Kennedy, Erin |
| Contributors | Rudner, Adam, Chakraborty, Pranesh |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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