Degree
Doctor of Philosophy (PhD)
Department
Biological Sciences
Document Type
Dissertation
Abstract
Ribosome biogenesis is an energetically costly process, and tight regulation is required for stoichiometric balance between components. This requires coordination of RNA polymerases I, II, and III. Lack of nutrients or the presence of stress leads to downregulation of ribosome biogenesis, a process for which mechanistic target of rapamycin complex I (mTORC1) is key. mTORC1 activity is communicated by means of specific transcription factors, and in yeast, which is a primary model system in which transcriptional coordination has been delineated, transcription factors involved in regulation of ribosomal protein genes include Fhl1p and its cofactors, Ifh1p and Crf1p. Ifh1p is an activator, whereas Crf1p has been implicated in maintaining the repressed state upon mTORC1 inhibition. Computational analyses of evolutionary relationships have indicated that Ifh1p and Crf1p descend from a common ancestor. In this dissertation, I present recent evidence, which suggests that Crf1p also functions as an activator. A new model has been proposed to consolidate available experimental evidence, which posits that Crf1p functions as an alternate activator to prevent the stronger activator Ifh1p from re-binding gene promoters upon mTORC1 inhibition. The correlation between retention of Crf1p in related yeast strains and duplication of ribosomal protein genes suggests that this backup activation may be important to ensure gene expression when Ifh1p is limiting. With ribosome biogenesis as a hallmark of cell growth, failure to control assembly of ribosomal components leads to several human pathologies. A comprehensive understanding of the mechanisms underlying this process is therefore of the essence. In this dissertation work I propose the physiological importance of Crf1p as a backup activator based on reduced expression observed for RiBi genes as well as severe growth defects of crf1Δ strain when posed with rapamycin based mTORC1 inhibition. I have also shown results suggesting the importance of IFHL-motif in recruiting the Fhl1p on the promoter. To conclude this work, I have presented experimental evidences suggesting redundancy in UTP22 regulation to maintain the basal expression of a RiBi gene under all circumstances.
Date
10-30-2023
Recommended Citation
Kumar, Sanjay, "YEAST CRF1P: AN ACTIVATOR IN NEED IS AN ACTIVATOR INDEED" (2023). LSU Doctoral Dissertations. 6301.
https://repository.lsu.edu/gradschool_dissertations/6301
Committee Chair
Anne Grove