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The Relationship Between Herpes Simp...

Mertens, Max Eldon.

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The Relationship Between Herpes Simplex Virus 1 and the Cellular DNA Damage Response.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Relationship Between Herpes Simplex Virus 1 and the Cellular DNA Damage Response./
Author:	Mertens, Max Eldon.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	162 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-09, Section: B.
Contained By:	Dissertations Abstracts International82-09B.
Subject:	Virology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28315312
ISBN:	9798582570363

The Relationship Between Herpes Simplex Virus 1 and the Cellular DNA Damage Response.
Mertens, Max Eldon.

The Relationship Between Herpes Simplex Virus 1 and the Cellular DNA Damage Response. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 162 p.

Source: Dissertations Abstracts International, Volume: 82-09, Section: B.

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

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

Cellular DNA is under constant threat from many different agents that can cause damage to the genome. Damage to the DNA can inhibit the ability of the cell to replicate its genome, which usually leads to death of the cell. Consequently, cells have evolved complex pathways of machinery, collectively termed the DNA damage response (DDR), with the sole purpose to fix any damaged DNA. DNA virus infection also activates the DDR. In this dissertation, we explore the relationship between the DDR and herpes simplex virus 1 (HSV-1). We describe the DDR to incoming and replicating viral genomes with an emphasis on two key DDR kinases: ATM and Chk2. We observed that the DDR is biphasic with incoming and replicating viral DNA activating Chk2 and ATM, respectively. Moreover, we were surprised to find that different DDR proteins had differing effects on the replication of the virus. Canonically, Mre11, encoded by the MRE11A gene and a component of the MRN complex, promotes the activation of ATM in response to double-stranded DNA breaks. However, disruption of MRE11A and ATM by CRISPR-Cas9 had opposing effects on HSV-1 replication, suggesting that the DDR to infection is much more nuanced than previously thought. We also describe a novel role for the p53 tumor suppressor in regulating the expression of a key HSV-1 DNA replication gene. Our findings also allowed us to compile a detailed model of the DDR to different stages of the HSV-1 lytic replication cycle, something not currently present in the field.In the appendix, we describe what we thought to be a novel antiviral signaling pathway. HSV-1 infection induces an innate antiviral response presumably though recognition of the viral genome in the nucleus. While the viral DNA is sensed in the nucleus, the signal is propagated to the cytosol by an unknown mechanism. Initial evidence suggested that the Sun1 nuclear envelope protein was involved in this propagation. However, upon more rigorous investigation, we found Sun1 to be dispensable. We discovered that an off-target effect was responsible for the initial phenotype.

ISBN: 9798582570363Subjects--Topical Terms:

642304
Virology.
Subjects--Index Terms:

Herpes Simplex 1

The Relationship Between Herpes Simplex Virus 1 and the Cellular DNA Damage Response.
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245 1 4 $a The Relationship Between Herpes Simplex Virus 1 and the Cellular DNA Damage Response.
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500 $a Source: Dissertations Abstracts International, Volume: 82-09, Section: B.
500 $a Advisor: Knipe, David M.
502 $a Thesis (Ph.D.)--Harvard University, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Cellular DNA is under constant threat from many different agents that can cause damage to the genome. Damage to the DNA can inhibit the ability of the cell to replicate its genome, which usually leads to death of the cell. Consequently, cells have evolved complex pathways of machinery, collectively termed the DNA damage response (DDR), with the sole purpose to fix any damaged DNA. DNA virus infection also activates the DDR. In this dissertation, we explore the relationship between the DDR and herpes simplex virus 1 (HSV-1). We describe the DDR to incoming and replicating viral genomes with an emphasis on two key DDR kinases: ATM and Chk2. We observed that the DDR is biphasic with incoming and replicating viral DNA activating Chk2 and ATM, respectively. Moreover, we were surprised to find that different DDR proteins had differing effects on the replication of the virus. Canonically, Mre11, encoded by the MRE11A gene and a component of the MRN complex, promotes the activation of ATM in response to double-stranded DNA breaks. However, disruption of MRE11A and ATM by CRISPR-Cas9 had opposing effects on HSV-1 replication, suggesting that the DDR to infection is much more nuanced than previously thought. We also describe a novel role for the p53 tumor suppressor in regulating the expression of a key HSV-1 DNA replication gene. Our findings also allowed us to compile a detailed model of the DDR to different stages of the HSV-1 lytic replication cycle, something not currently present in the field.In the appendix, we describe what we thought to be a novel antiviral signaling pathway. HSV-1 infection induces an innate antiviral response presumably though recognition of the viral genome in the nucleus. While the viral DNA is sensed in the nucleus, the signal is propagated to the cytosol by an unknown mechanism. Initial evidence suggested that the Sun1 nuclear envelope protein was involved in this propagation. However, upon more rigorous investigation, we found Sun1 to be dispensable. We discovered that an off-target effect was responsible for the initial phenotype.
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650 4 $a Genetics. $3 530508
653 $a Herpes Simplex 1
653 $a Cellular DNA
653 $a DNA Damage Response
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690 $a 0369
710 2 $a Harvard University. $b Medical Sciences. $3 3181716
773 0 $t Dissertations Abstracts International $g 82-09B.
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792 $a 2021
793 $a English
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