東華大學圖書館 |

Regulation at the Nuclear Envelope: Degradation and Remodeling in S. Cerevisiae.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Regulation at the Nuclear Envelope: Degradation and Remodeling in S. Cerevisiae./
作者:	Koch, Bailey Anne.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	120 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-02, Section: B.
Contained By:	Dissertations Abstracts International82-02B.
標題:	Cellular biology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27737614
ISBN:	9798662466531

Regulation at the Nuclear Envelope: Degradation and Remodeling in S. Cerevisiae.
Koch, Bailey Anne.

Regulation at the Nuclear Envelope: Degradation and Remodeling in S. Cerevisiae. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 120 p.

Source: Dissertations Abstracts International, Volume: 82-02, Section: B.

Thesis (Ph.D.)--The Florida State University, 2020.

.

The eukaryotic genome is encased by a double membrane structure, the nuclear envelope (NE), forming the outer structure of the nucleus. The NE is highly dynamic and separates the nucleoplasm from the cytoplasm. The NE is involved in processes such as the maintenance of nuclear architecture, chromatin organization, DNA replication, gene expression, and signal transduction. Maintaining NE dynamics is crucial for cellular health, as compromised NE integrity is a key indicator of various pathologies and also of cellular aging. The outer nuclear membrane (ONM) of the NE is contiguous with the endoplasmic reticulum (ER), whereas the inner nuclear membrane (INM) is compositionally distinct but contiguous with the ONM through nuclear pore complexes (NPCs). In order to ensure homeostasis between these membranes, degradation systems are in place at both the INM and ONM/ER. INM-associated degradation (INMAD) is required for both protein quality control and regulated proteolysis of INM proteins. Two INMAD pathways utilizing the membrane bound E3 ligase complexes, containing either Doa10 or Asi1-3, have been previously defined, and we have revealed a novel branch mediated by the nuclear ligase anaphase promoting complex/cyclosome (APC/C). APC/C-mediated INMAD functions with the E2 ligases Ubc6 and Ubc7, and is responsible for the degradation of the SUN protein, Mps3, through the ubiquitin proteasome. Mps3 is the sole SUN protein in budding yeast and physically interacts with the KASH-like protein within the luminal space of the NE. This interaction creates the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex spans the NE and is critical for transducing mechanical forces from the cytoskeleton to the nucleus. Dysregulation of the LINC complex, such as the overaccumulation of SUN proteins, in mammals leads to catastrophic disruption of NE integrity, resulting in a range of disorders termed laminopathies. Our finding that the budding yeast SUN protein is regulated by APC/C has implications for the conserved nature of INMAD processes and is crucial to understanding many laminopathies in humans. Another complex crucial for maintaining NE integrity that spans the NE is the NPC. NPCs are large multi-subunit structures that form an aqueous channel embedded in the NE, allowing for passage between the nucleus and cytoplasm. Functional NPCs are essential for nucleocytoplasmic transport, a process required for maintaining NE integrity and cellular health. NPCs were previously hypothesized to be extremely stable complexes, but recent work in budding yeast meiosis has revealed a unique aggregation of NPCs during anaphase II that is believed to occur as a quality control mechanism, constricting NPCs from the gametes. The aggregated NPCs were found to cluster with senescence factors, including oxidatively damaged protein aggregates and rDNA circles, implying this sequestration is a reorganization of the NE and functions to rejuvenate the resulting daughter cells. However, at the molecular level neither the mechanism regulating NE reorganization, nor how daughter cells are rejuvenated are entirely clear. We have found that the meiotic sequestration of NPCs (MSON) compartment is dependent on the Endosomal Sorting Complexes Required for Transport (ESCRT)-III complex, providing the first mechanistic insight into meiotic NE reorganization with implications for cellular rejuvenation. During meiosis, the LEM-domain protein, Heh1, and the ESCRT-III component, Chm7, function with the AAA-ATPase Vps4 to form constriction sites similar to those observed during asymmetric cell division in mitosis. Constriction of the NPCs is an essential process in meiosis to ensure the rejuvenation of gametes, as hindering this sequestration results in a deterioration of the daughter cells' replicative lifespans. Our finding that ESCRT-III/Vps4 mediates the sequestration of NPCs during meiosis II is relevant to the understanding of aging and other NPC related diseases such as early-onset dystonia.Maintaining nuclear integrity is a critical factor in cellular health, mediated in part by the LINC complex and NPC, both of which are highly conserved in composition and in function. Perturbation of the regulatory mechanisms acting on these complexes leads to a variety of diseases and aging disorders in humans, underlining the significance of elucidating these factors in budding yeast. Our work establishes the first known case of APC/C-mediated protein degradation at the NE, and also the first example of an ESCRT-III mediated mechanism for meiotic NE reorganization. These processes are critical for coordinating nuclear morphogenesis and cell-cycle progression, while providing mechanistic insight into the poorly understood phenomena of cellular rejuvenation. These studies have broad implications, therefore, for better understanding of laminopathies and age-associated diseases in humans.

ISBN: 9798662466531Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Nuclear envelope

Regulation at the Nuclear Envelope: Degradation and Remodeling in S. Cerevisiae.
LDR:06060nmm a2200373 4500 001 2399856
005 20240916070001.5
006 m o d
007 cr#unu||||||||
008 251215s2020 ||||||||||||||||| ||eng d
020 $a 9798662466531
035 $a (MiAaPQ)AAI27737614
035 $a AAI27737614
040 $a MiAaPQ $c MiAaPQ
100 1 $a Koch, Bailey Anne. $0 (orcid)0000-0002-0326-2079 $3 3769831
245 1 0 $a Regulation at the Nuclear Envelope: Degradation and Remodeling in S. Cerevisiae.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 120 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-02, Section: B.
500 $a Advisor: Yu, Hong-Guo.
502 $a Thesis (Ph.D.)--The Florida State University, 2020.
506 $a .
520 $a The eukaryotic genome is encased by a double membrane structure, the nuclear envelope (NE), forming the outer structure of the nucleus. The NE is highly dynamic and separates the nucleoplasm from the cytoplasm. The NE is involved in processes such as the maintenance of nuclear architecture, chromatin organization, DNA replication, gene expression, and signal transduction. Maintaining NE dynamics is crucial for cellular health, as compromised NE integrity is a key indicator of various pathologies and also of cellular aging. The outer nuclear membrane (ONM) of the NE is contiguous with the endoplasmic reticulum (ER), whereas the inner nuclear membrane (INM) is compositionally distinct but contiguous with the ONM through nuclear pore complexes (NPCs). In order to ensure homeostasis between these membranes, degradation systems are in place at both the INM and ONM/ER. INM-associated degradation (INMAD) is required for both protein quality control and regulated proteolysis of INM proteins. Two INMAD pathways utilizing the membrane bound E3 ligase complexes, containing either Doa10 or Asi1-3, have been previously defined, and we have revealed a novel branch mediated by the nuclear ligase anaphase promoting complex/cyclosome (APC/C). APC/C-mediated INMAD functions with the E2 ligases Ubc6 and Ubc7, and is responsible for the degradation of the SUN protein, Mps3, through the ubiquitin proteasome. Mps3 is the sole SUN protein in budding yeast and physically interacts with the KASH-like protein within the luminal space of the NE. This interaction creates the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex spans the NE and is critical for transducing mechanical forces from the cytoskeleton to the nucleus. Dysregulation of the LINC complex, such as the overaccumulation of SUN proteins, in mammals leads to catastrophic disruption of NE integrity, resulting in a range of disorders termed laminopathies. Our finding that the budding yeast SUN protein is regulated by APC/C has implications for the conserved nature of INMAD processes and is crucial to understanding many laminopathies in humans. Another complex crucial for maintaining NE integrity that spans the NE is the NPC. NPCs are large multi-subunit structures that form an aqueous channel embedded in the NE, allowing for passage between the nucleus and cytoplasm. Functional NPCs are essential for nucleocytoplasmic transport, a process required for maintaining NE integrity and cellular health. NPCs were previously hypothesized to be extremely stable complexes, but recent work in budding yeast meiosis has revealed a unique aggregation of NPCs during anaphase II that is believed to occur as a quality control mechanism, constricting NPCs from the gametes. The aggregated NPCs were found to cluster with senescence factors, including oxidatively damaged protein aggregates and rDNA circles, implying this sequestration is a reorganization of the NE and functions to rejuvenate the resulting daughter cells. However, at the molecular level neither the mechanism regulating NE reorganization, nor how daughter cells are rejuvenated are entirely clear. We have found that the meiotic sequestration of NPCs (MSON) compartment is dependent on the Endosomal Sorting Complexes Required for Transport (ESCRT)-III complex, providing the first mechanistic insight into meiotic NE reorganization with implications for cellular rejuvenation. During meiosis, the LEM-domain protein, Heh1, and the ESCRT-III component, Chm7, function with the AAA-ATPase Vps4 to form constriction sites similar to those observed during asymmetric cell division in mitosis. Constriction of the NPCs is an essential process in meiosis to ensure the rejuvenation of gametes, as hindering this sequestration results in a deterioration of the daughter cells' replicative lifespans. Our finding that ESCRT-III/Vps4 mediates the sequestration of NPCs during meiosis II is relevant to the understanding of aging and other NPC related diseases such as early-onset dystonia.Maintaining nuclear integrity is a critical factor in cellular health, mediated in part by the LINC complex and NPC, both of which are highly conserved in composition and in function. Perturbation of the regulatory mechanisms acting on these complexes leads to a variety of diseases and aging disorders in humans, underlining the significance of elucidating these factors in budding yeast. Our work establishes the first known case of APC/C-mediated protein degradation at the NE, and also the first example of an ESCRT-III mediated mechanism for meiotic NE reorganization. These processes are critical for coordinating nuclear morphogenesis and cell-cycle progression, while providing mechanistic insight into the poorly understood phenomena of cellular rejuvenation. These studies have broad implications, therefore, for better understanding of laminopathies and age-associated diseases in humans.
590 $a School code: 0071.
650 4 $a Cellular biology. $3 3172791
650 4 $a Genetics. $3 530508
650 4 $a Biophysics. $3 518360
653 $a Nuclear envelope
653 $a Outer nuclear membrane
653 $a Endoplasmic reticulum
690 $a 0379
690 $a 0369
690 $a 0786
710 2 $a The Florida State University. $b Biological Science. $3 3182932
773 0 $t Dissertations Abstracts International $g 82-02B.
790 $a 0071
791 $a Ph.D.
792 $a 2020
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27737614