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Induction of Markers of DNA Damage S...

Wang'ondu, Ruth.

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Induction of Markers of DNA Damage Signaling upon Reactivation of Epstein-Barr Virus: A Novel Role for ZEBRA and the Pre-replicative Phase of the Viral Lytic Cycle.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Induction of Markers of DNA Damage Signaling upon Reactivation of Epstein-Barr Virus: A Novel Role for ZEBRA and the Pre-replicative Phase of the Viral Lytic Cycle./
Author:	Wang'ondu, Ruth.
Description:	215 p.
Notes:	Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.
Contained By:	Dissertation Abstracts International76-11B(E).
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3663682
ISBN:	9781321965476

Induction of Markers of DNA Damage Signaling upon Reactivation of Epstein-Barr Virus: A Novel Role for ZEBRA and the Pre-replicative Phase of the Viral Lytic Cycle.
Wang'ondu, Ruth.

Induction of Markers of DNA Damage Signaling upon Reactivation of Epstein-Barr Virus: A Novel Role for ZEBRA and the Pre-replicative Phase of the Viral Lytic Cycle. - 215 p.

Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.

Thesis (Ph.D.)--Yale University, 2015.

Epstein Barr virus (EBV), like other oncogenic viruses, manipulates cellular DNA damage signaling pathways during its life cycle. Activation of markers of DNA damage signaling during the EBV lytic cycle is hypothesized to occur in response to large amounts of exogenous double stranded DNA products generated during lytic EBV DNA replication. Here I show that viral DNA replication, per se, may not be the only trigger for induction of DNA damage signaling markers during the EBV lytic cycle. To study induction of DNA damage signaling markers during the pre-replicative stage of the EBV lifecycle, I relied on the characteristic, diffuse, nuclear distribution of early lytic proteins, the use of phosphonoacetic acid, an EBV replication inhibitor, and target cells that did not replicate EBV or lack EBV DNA. I showed that ATM and at least one of three substrates of ATM, namely H2AX, 53BP1, or P53, are phosphorylated upon EBV lytic reactivation in EBV-positive HEK and Burkitt lymphoma cell lines. Phosphorylated forms of ATM and its substrates were induced in lytically reactivated EBV positive cells during the pre-replicative state as well as during EBV DNA replication. I found that ZEBRA, a bZIP transcription factor that is sufficient and indispensable for EBV lytic replication, was capable of activating phosphorylation of ATM and H2AX independent of other EBV gene products. Two ZEBRA mutants deficient in DNA binding did not induce markers of DNA damage signaling. ATM and H2AX phosphorylation induced prior to EBV replication may be critical for creating a microenvironment conducive for progression of the lytic cycle and might also contribute to oncogenesis.

ISBN: 9781321965476Subjects--Topical Terms:

3172791
Cellular biology.

Induction of Markers of DNA Damage Signaling upon Reactivation of Epstein-Barr Virus: A Novel Role for ZEBRA and the Pre-replicative Phase of the Viral Lytic Cycle.
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520 $a Epstein Barr virus (EBV), like other oncogenic viruses, manipulates cellular DNA damage signaling pathways during its life cycle. Activation of markers of DNA damage signaling during the EBV lytic cycle is hypothesized to occur in response to large amounts of exogenous double stranded DNA products generated during lytic EBV DNA replication. Here I show that viral DNA replication, per se, may not be the only trigger for induction of DNA damage signaling markers during the EBV lytic cycle. To study induction of DNA damage signaling markers during the pre-replicative stage of the EBV lifecycle, I relied on the characteristic, diffuse, nuclear distribution of early lytic proteins, the use of phosphonoacetic acid, an EBV replication inhibitor, and target cells that did not replicate EBV or lack EBV DNA. I showed that ATM and at least one of three substrates of ATM, namely H2AX, 53BP1, or P53, are phosphorylated upon EBV lytic reactivation in EBV-positive HEK and Burkitt lymphoma cell lines. Phosphorylated forms of ATM and its substrates were induced in lytically reactivated EBV positive cells during the pre-replicative state as well as during EBV DNA replication. I found that ZEBRA, a bZIP transcription factor that is sufficient and indispensable for EBV lytic replication, was capable of activating phosphorylation of ATM and H2AX independent of other EBV gene products. Two ZEBRA mutants deficient in DNA binding did not induce markers of DNA damage signaling. ATM and H2AX phosphorylation induced prior to EBV replication may be critical for creating a microenvironment conducive for progression of the lytic cycle and might also contribute to oncogenesis.
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