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Protein Acetylation as a Regulatory ...

Murray, Laura Alexis.

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Protein Acetylation as a Regulatory Toggle During Viral Infection and DNA Repair.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Protein Acetylation as a Regulatory Toggle During Viral Infection and DNA Repair./
Author:	Murray, Laura Alexis.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	254 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-11, Section: B.
Contained By:	Dissertations Abstracts International82-11B.
Subject:	Molecular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28323071
ISBN:	9798708759306

Protein Acetylation as a Regulatory Toggle During Viral Infection and DNA Repair.
Murray, Laura Alexis.

Protein Acetylation as a Regulatory Toggle During Viral Infection and DNA Repair. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 254 p.

Source: Dissertations Abstracts International, Volume: 82-11, Section: B.

Thesis (Ph.D.)--Princeton University, 2021.

This item must not be sold to any third party vendors.

Post-translational modifications (PTMs) underlie numerous mechanisms that dynamically regulate proteins in subcellular space and time. A prevalent protein PTM is lysine acetylation, a modification with versatile regulatory roles in protein function, subcellular localization, and stability. Although accumulating evidence points to a role for acetylation during viral infections, the knowledge of the underlying mechanisms or contributions to host defense and viral replication events remained limited. To characterize the functions of acetylation in the context of pathogen infection, I focused on the prevalent betaherpesvirus human cytomegalovirus (HCMV). We integrated global acetylome analysis with microscopy, genetic manipulation, and molecular virology assays. Anti-acetyl-lysine immunoaffinity purification followed by mass spectrometry allowed the identification of temporal and spatial alterations in protein acetylation in a site-specific manner on both host and viral proteins over the time course of HCMV replication. A large number of previously unrecognized acetylations on viral proteins was detected, and we discovered the antiviral function for the acetylation of the tegument protein pUL26. Among the distinct acetylation trends that we identified for cellular proteins, we observed a near-global increase in acetylation on mitochondrial proteins. Late in infection, acetylation was increased on a subset of specific nuclear proteins, including lamins. We determined that lamin B1 (LMNB1) acetylation provides a host defense mechanism by inhibiting nuclear periphery disruption and impeding viral capsid nuclear egress.Given the known functions of lamins in cell cycle progression and DNA repair, I next asked whether LMNB1 acetylation plays a broader role as a regulatory toggle for homeostatic nuclear periphery processes. To address this hypothesis, we integrated proximity labeling followed by mass spectrometry, microscopy, flow cytometry, and DNA repair assays. We determined that LMNB1 acetylation impedes the progression of the cell cycle by activating the G1/S cell cycle checkpoint. In the presence of DNA damage, this acetylation slows DNA repair by delaying the recruitment of the canonical nonhomologous end joining repair factor 53BP1 and biases repair towards alternative repair pathways. Altogether, this thesis provides insight into the dynamics of protein acetylation during HCMV infection and elucidates a functional role for LMNB1 acetylation during herpesvirus infection and in DNA repair.

ISBN: 9798708759306Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Acetylation

Protein Acetylation as a Regulatory Toggle During Viral Infection and DNA Repair.
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245 1 0 $a Protein Acetylation as a Regulatory Toggle During Viral Infection and DNA Repair.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2021
300 $a 254 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-11, Section: B.
500 $a Advisor: Cristea, Ileana M.
502 $a Thesis (Ph.D.)--Princeton University, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Post-translational modifications (PTMs) underlie numerous mechanisms that dynamically regulate proteins in subcellular space and time. A prevalent protein PTM is lysine acetylation, a modification with versatile regulatory roles in protein function, subcellular localization, and stability. Although accumulating evidence points to a role for acetylation during viral infections, the knowledge of the underlying mechanisms or contributions to host defense and viral replication events remained limited. To characterize the functions of acetylation in the context of pathogen infection, I focused on the prevalent betaherpesvirus human cytomegalovirus (HCMV). We integrated global acetylome analysis with microscopy, genetic manipulation, and molecular virology assays. Anti-acetyl-lysine immunoaffinity purification followed by mass spectrometry allowed the identification of temporal and spatial alterations in protein acetylation in a site-specific manner on both host and viral proteins over the time course of HCMV replication. A large number of previously unrecognized acetylations on viral proteins was detected, and we discovered the antiviral function for the acetylation of the tegument protein pUL26. Among the distinct acetylation trends that we identified for cellular proteins, we observed a near-global increase in acetylation on mitochondrial proteins. Late in infection, acetylation was increased on a subset of specific nuclear proteins, including lamins. We determined that lamin B1 (LMNB1) acetylation provides a host defense mechanism by inhibiting nuclear periphery disruption and impeding viral capsid nuclear egress.Given the known functions of lamins in cell cycle progression and DNA repair, I next asked whether LMNB1 acetylation plays a broader role as a regulatory toggle for homeostatic nuclear periphery processes. To address this hypothesis, we integrated proximity labeling followed by mass spectrometry, microscopy, flow cytometry, and DNA repair assays. We determined that LMNB1 acetylation impedes the progression of the cell cycle by activating the G1/S cell cycle checkpoint. In the presence of DNA damage, this acetylation slows DNA repair by delaying the recruitment of the canonical nonhomologous end joining repair factor 53BP1 and biases repair towards alternative repair pathways. Altogether, this thesis provides insight into the dynamics of protein acetylation during HCMV infection and elucidates a functional role for LMNB1 acetylation during herpesvirus infection and in DNA repair.
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650 4 $a Immunology. $3 611031
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653 $a Acetylation
653 $a Herpesvirus
653 $a Lamin B1
653 $a Nuclear integrity
653 $a Protein-protein interactions
653 $a Proteomics
653 $a Post-translational modifications
653 $a Human cytomegalovirus
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710 2 $a Princeton University. $b Molecular Biology. $3 2101701
773 0 $t Dissertations Abstracts International $g 82-11B.
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