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Investigation of Nuclear Envelope-As...

Sears, Rhiannon Marie.

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Investigation of Nuclear Envelope-Associated Progeria Proteins During Nuclear Envelope Rupture.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Investigation of Nuclear Envelope-Associated Progeria Proteins During Nuclear Envelope Rupture./
Author:	Sears, Rhiannon Marie.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2022,
Description:	160 p.
Notes:	Source: Dissertations Abstracts International, Volume: 84-06, Section: B.
Contained By:	Dissertations Abstracts International84-06B.
Subject:	Cellular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29999575
ISBN:	9798363500855

Investigation of Nuclear Envelope-Associated Progeria Proteins During Nuclear Envelope Rupture.
Sears, Rhiannon Marie.

Investigation of Nuclear Envelope-Associated Progeria Proteins During Nuclear Envelope Rupture. - Ann Arbor : ProQuest Dissertations & Theses, 2022 - 160 p.

Source: Dissertations Abstracts International, Volume: 84-06, Section: B.

Thesis (Ph.D.)--University of South Dakota, 2022.

The nuclear envelope (NE) is a specialized extension of the endoplasmic reticulum critical for the proper protection and organization of the genome. This interphase-only structure is host to several proteins and their interacting constituents that have various and diverse cellular roles. Mutations in NE constituents are associated with several human diseases. A subset of these diseases, known as progeria syndromes, are characterized by the premature presentation of physiological aging in a variety of tissues. Mutations in the genes LMNA and BANF1, which encode the A-type lamins and barrier-to-autointegration factor (BAF), can lead to these multisystem progeroid diseases. Though the underlying mechanisms of disease are poorly understood, progeria patient-derived cells show evidence of NE disruptions that result in NE ruptures and the loss of proper nucleocytoplasmic compartmentalization. Previously, we showed BAF localizes to sites of nuclear rupture and is required for recruiting NE-repair machinery. Here, we show a mobile, nucleoplasmic population of A-type lamins is recruited to ruptures in a BAF-dependent manner via BAF's association with the Ig-like β fold domain. Furthermore, disease mutations in A-type lamins that disrupt their mobility and/or interaction with BAF also disrupt their ability to target to nuclear ruptures. Similarly, a progeric BAF is unable to recruit A-type lamins to ruptures despite being able to target to NE rupture sites itself. Further analyses of the lamin disease-associated mutants revealed functional discrepancies during the nuclear rupture process.These data show that disruption of BAF and A-type lamin interactions compromise lamin recruitment to NE ruptures and may alter the proper mechanisms needed for efficient NE rupture response and repair, potentially contributing to disease phenotypes. Collectively, the results of these studies illustrate the value in comparative studies between laminopathy-associated disease mutations, especially those that result in the same disease.

ISBN: 9798363500855Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Barrier-to-autointegration factor

Investigation of Nuclear Envelope-Associated Progeria Proteins During Nuclear Envelope Rupture.
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245 1 0 $a Investigation of Nuclear Envelope-Associated Progeria Proteins During Nuclear Envelope Rupture.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2022
300 $a 160 p.
500 $a Source: Dissertations Abstracts International, Volume: 84-06, Section: B.
500 $a Advisor: Roux, Kyle J.;Chandrasekar, Indra.
502 $a Thesis (Ph.D.)--University of South Dakota, 2022.
520 $a The nuclear envelope (NE) is a specialized extension of the endoplasmic reticulum critical for the proper protection and organization of the genome. This interphase-only structure is host to several proteins and their interacting constituents that have various and diverse cellular roles. Mutations in NE constituents are associated with several human diseases. A subset of these diseases, known as progeria syndromes, are characterized by the premature presentation of physiological aging in a variety of tissues. Mutations in the genes LMNA and BANF1, which encode the A-type lamins and barrier-to-autointegration factor (BAF), can lead to these multisystem progeroid diseases. Though the underlying mechanisms of disease are poorly understood, progeria patient-derived cells show evidence of NE disruptions that result in NE ruptures and the loss of proper nucleocytoplasmic compartmentalization. Previously, we showed BAF localizes to sites of nuclear rupture and is required for recruiting NE-repair machinery. Here, we show a mobile, nucleoplasmic population of A-type lamins is recruited to ruptures in a BAF-dependent manner via BAF's association with the Ig-like β fold domain. Furthermore, disease mutations in A-type lamins that disrupt their mobility and/or interaction with BAF also disrupt their ability to target to nuclear ruptures. Similarly, a progeric BAF is unable to recruit A-type lamins to ruptures despite being able to target to NE rupture sites itself. Further analyses of the lamin disease-associated mutants revealed functional discrepancies during the nuclear rupture process.These data show that disruption of BAF and A-type lamin interactions compromise lamin recruitment to NE ruptures and may alter the proper mechanisms needed for efficient NE rupture response and repair, potentially contributing to disease phenotypes. Collectively, the results of these studies illustrate the value in comparative studies between laminopathy-associated disease mutations, especially those that result in the same disease.
590 $a School code: 0203.
650 4 $a Cellular biology. $3 3172791
650 4 $a Molecular biology. $3 517296
650 4 $a Aging. $3 543123
653 $a Barrier-to-autointegration factor
653 $a Lamin
653 $a LMNA
653 $a Nuclear envelope
653 $a Nuclear rupture
653 $a Progeria
690 $a 0379
690 $a 0307
690 $a 0493
710 2 $a University of South Dakota. $b Basic Biomedical Sciences. $3 3183033
773 0 $t Dissertations Abstracts International $g 84-06B.
790 $a 0203
791 $a Ph.D.
792 $a 2022
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29999575