DNA damage induced SUMOylation regulates intranuclear protein quality control in Saccharomyces cerevisiae
department or school: Medicine, Faculty of
department or school: Medical Genetics, Department of
data provider: DSpace
degree campus: UBCV
creator: Kumar, Arun
issued: 2024-01-11T18:18:36Z
issued: 2023
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Proteostasis is critical for cell survival. Exposure to stressors such as DNA damage, heat, mutations, or ageing can accumulate proteins in non-native conformations. The accumulation of these misfolded proteins, through either gain- or loss-of-function, disrupts vital cellular processes. This is notably evident in neurodegenerative diseases such as Alzheimer’s, and Parkinson's which are linked to protein aggregation pathology. Therefore, cells strive to maintain a healthy proteome which is achieved through a complex network of protein quality control (PQC) circuits. Traditionally, PQC was thought to rely on two major pathways: molecular chaperones for refolding and proteolytic systems for degradation. However, this perspective has been challenged with the discovery of protein sequestration. Under severe stress conditions that overwhelm PQC systems, misfolded proteins are spatially sequestered to specialized and distinct membrane-less inclusions within the cell. This spatial compartmentalization represents a crucial aspect of PQC, facilitating the storage of disassembled or non-native proteins until they can be either refolded or degraded in a regulated manner. The model organism Saccharomyces cerevisiae or budding yeast has three well-established sequestration sites – the Insoluble PrOtein Deposit (IPOD), the JUxtaNuclear Quality control (JUNQ) site and the IntraNuclear Quality control (INQ) site. Although substantial efforts have contributed to identifying key proteins involved in the formation and dissolution of these sequestration sites, our understanding of the regulation and dynamics of INQ remains incomplete. In my thesis, I provide a comprehensive analysis of all proteins that have been found at INQ. Furthermore, I explore different pathways and stressors to expand our knowledge of the factors governing INQ formation. To do so, I first characterize Rpd3, a histone deacetylase, as a novel INQ marker and use its localization as a proxy for INQ levels. Through m…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/87208
note: DNA damage induced SUMOylation regulates intranuclear protein quality control in Saccharomyces cerevisiae by ARUN KUMAR B.Tech., Manipal Institute of Technology, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (MEDICAL GENETICS) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2023 © Arun Kumar, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: DNA damage induced SUMOylation regulates intranuclear protein quality control in Saccharomyces cerevisiae submitted by Arun Kumar in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Medical Genetics Examining Committee: Peter Stirling, Associate Professor, Department of Medical Genetics, UBC Supervisor Elizabeth Conibear, Professor, Department of Medical Genetics, UBC Supervisory Committee Member Pamela Hoodless, Professor, Department of Medical Genetics, UBC University Examiner Corey Nislow, Professor, Faculty of Pharmaceutical Sciences, UBC University Examiner Additional Supervisory Committee Members: Thibault Mayor, Professor, Department of Biochemistry and Molecular Biology, UBC Supervisory Committee Member Philip Hieter, Professor, Department of Medical Genetics, UBC Supervisory Committee Member iii Abstract Proteostasis is critical for cell survival. Exposure to stressors such as DNA damage, heat, mutations, or ageing can accumulate proteins in non-native conformations. The accumulation of these misfolded proteins, through either gain- or loss-of-function, disrupts vital cellular processes. This is notably evident in neurodegenerative diseases such as Alzheimer’s, and Parkinson's which are linked to protein aggregation pathology. Therefore, cells strive to maintain a healthy proteome which is achieved through a complex network of protein quality control …
has type: Thesis/Dissertation
date issued: 2024-05
is shown at: 10.14288/1.0438642
language: eng
degree discipline: Medical Genetics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Stirling, Peter C.
type: Text
identifier URI: http://hdl.handle.net/2429/87208