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Regulation of Nuclear Envelope Remodeling by the ESCRT Machinery.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Regulation of Nuclear Envelope Remodeling by the ESCRT Machinery./
Author:	Shankar, Raakhee.
Description:	1 online resource (250 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 83-03, Section: B.
Contained By:	Dissertations Abstracts International83-03B.
Subject:	Cellular biology. -
Online resource:	click for full text (PQDT)
ISBN:	9798538120857

Regulation of Nuclear Envelope Remodeling by the ESCRT Machinery.
Shankar, Raakhee.

Regulation of Nuclear Envelope Remodeling by the ESCRT Machinery. - 1 online resource (250 pages)

Source: Dissertations Abstracts International, Volume: 83-03, Section: B.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2021.

Includes bibliographical references

The endosomal sorting complex required for transport (ESCRT) machinery participates in a wide range of cellular processes. These processes include multivesicular endosome biogenesis, nuclear envelope reformation and repair, cytokinesis, plasma membrane repair, among others. The common thread between these diverse cellular processes is that the ESCRT machinery remodels membranes displaying similar topology. In the work presented in this thesis, I focus on elucidating the mechanisms by which the ESCRT machinery maintains the nuclear envelope (NE) integrity.The eukaryotic NE encloses the genome and forms a barrier allowing selective transport of material between the nucleus and the cytoplasm. This barrier is disrupted when the cell undergoes open mitosis. It is therefore necessary to reform the NE on mitotic exit. The ESCRT machinery has been implicated in remodeling the NE after mitosis to reestablish nuclear compartmentalization. Additional studies suggest that in migrating cells, interphase NE undergoes transient ruptures. Rapid membrane remodeling is required in such cases to maintain genome integrity. Failure to restore the nuclear barrier function may result in DNA damage.In this work I utilize the stereotypic first mitotic division of the C. elegans embryo to investigate the quality control mechanisms present during NE reformation. Work presented in both Chapters 2 and 3 are studies done in a developing organism. Collaborative work presented in Chapter 2 reveals a role for CNEP-1 which regulates synthesis of glycerolipids, and in conjunction with the ESCRT-III machinery limits ER sheet incorporation at NE ruptures following lamin depletion. In Chapter 3 I investigate the role of CHMP7, an adaptor for the ESCRT machinery at the NE, in regulating the ESCRT-III machinery at the reforming NE after mitosis as well as under conditions with a compromised nuclear lamina. I show that in C. elegans, CHMP7 localizes to the inner nuclear membrane throughout interphase. This is striking because in yeast and mammalian cell lines, CHMP7 localizes to the ER and localizes at the reforming NE transiently during late anaphase. Using electron tomography, I demonstrate that impairment in ESCRT function leads to formation of NE invaginations originating from the inner nuclear membrane. These tubules are enriched with INM proteins including LEM2 (Ce MAN1), LMN1 (lamin), SUN1 (LINC complex) as well as every subunit of the ESCRT-III machinery except VPS20. I also identify the presence of intranuclear vesicles emanating from the INM tubules suggesting that the ESCRT machinery is involved in pruning these tubules to maintain INM integrity. Embryos lacking CHMP7 do not display defects in NE closure suggesting the presence of multiple redundant mechanisms to ensure NE closure. To that effect, I propose a role for VPS60/CHMP5 in maintaining the health of C. elegans gonad by regulating germline apoptosis.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798538120857Subjects--Topical Terms:

1148666
Cellular biology.
Subjects--Index Terms:

C. elegansIndex Terms--Genre/Form:

554714
Electronic books.

Regulation of Nuclear Envelope Remodeling by the ESCRT Machinery.
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520 $a The endosomal sorting complex required for transport (ESCRT) machinery participates in a wide range of cellular processes. These processes include multivesicular endosome biogenesis, nuclear envelope reformation and repair, cytokinesis, plasma membrane repair, among others. The common thread between these diverse cellular processes is that the ESCRT machinery remodels membranes displaying similar topology. In the work presented in this thesis, I focus on elucidating the mechanisms by which the ESCRT machinery maintains the nuclear envelope (NE) integrity.The eukaryotic NE encloses the genome and forms a barrier allowing selective transport of material between the nucleus and the cytoplasm. This barrier is disrupted when the cell undergoes open mitosis. It is therefore necessary to reform the NE on mitotic exit. The ESCRT machinery has been implicated in remodeling the NE after mitosis to reestablish nuclear compartmentalization. Additional studies suggest that in migrating cells, interphase NE undergoes transient ruptures. Rapid membrane remodeling is required in such cases to maintain genome integrity. Failure to restore the nuclear barrier function may result in DNA damage.In this work I utilize the stereotypic first mitotic division of the C. elegans embryo to investigate the quality control mechanisms present during NE reformation. Work presented in both Chapters 2 and 3 are studies done in a developing organism. Collaborative work presented in Chapter 2 reveals a role for CNEP-1 which regulates synthesis of glycerolipids, and in conjunction with the ESCRT-III machinery limits ER sheet incorporation at NE ruptures following lamin depletion. In Chapter 3 I investigate the role of CHMP7, an adaptor for the ESCRT machinery at the NE, in regulating the ESCRT-III machinery at the reforming NE after mitosis as well as under conditions with a compromised nuclear lamina. I show that in C. elegans, CHMP7 localizes to the inner nuclear membrane throughout interphase. This is striking because in yeast and mammalian cell lines, CHMP7 localizes to the ER and localizes at the reforming NE transiently during late anaphase. Using electron tomography, I demonstrate that impairment in ESCRT function leads to formation of NE invaginations originating from the inner nuclear membrane. These tubules are enriched with INM proteins including LEM2 (Ce MAN1), LMN1 (lamin), SUN1 (LINC complex) as well as every subunit of the ESCRT-III machinery except VPS20. I also identify the presence of intranuclear vesicles emanating from the INM tubules suggesting that the ESCRT machinery is involved in pruning these tubules to maintain INM integrity. Embryos lacking CHMP7 do not display defects in NE closure suggesting the presence of multiple redundant mechanisms to ensure NE closure. To that effect, I propose a role for VPS60/CHMP5 in maintaining the health of C. elegans gonad by regulating germline apoptosis.
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