Persistent Link:
http://hdl.handle.net/10150/195141
Title:
The Role of ADP-Ribosylation in Mitochondria-Mediated Cell Death
Author:
Whatcott, Clifford Jason
Issue Date:
2009
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Poly(ADP)ribose (PAR) metabolism is essential to many cellular functions, including the maintenance of genomic integrity, the regulation of cell death mechanisms, as well as the regulation of gene expression. Recent work has uncovered many new players in the expanding effort to understand PAR metabolism and its cellular impact. PARP-1, the prototypical poly(ADP)ribose polymerase, was the first to be discovered, and has since been shown to be vital in the cellular response to DNA damage. Indeed, one report demonstrating that PARP-1 activation is required for apoptosis-inducing factor (AIF) release from mitochondria uncovered a novel link between DNA damage and signaling for cell death. The events following PARP activation, leading to signaling for AIF release, however, are still poorly understood. Based on our observations, we have developed a model to explain the nuclear/mitochondrial crosstalk that occurs following PARP activation. The work presented here answers several important questions regarding the relationship between ADP-ribose metabolism and mitochondria, including the role of PAR in signaling for the release of AIF, the presence of ADP-ribose metabolism protein members in mitochondria, and mitochondrial transcriptional effects following PARP activation. This work presents several novel findings, including the first report of a mitochondrial matrix isoform of poly(ADP-ribose) glycohydrolase (PARG) as well as direct evidence of mitochondria-associated PARP activity. Furthermore, it provides evidence for a novel effect of PARP-1 activation, in the specific transcriptional upregulation of the mitochondrial gene, NADH dehydrogenase, subunit 1 (ND1). Our data is consistent with the hypothesis that uncontrolled PARP activity results in energy metabolism dysfunction and cell death. Furthermore, it supports a model in which PARP activity is required for normal transcriptional responses in mitochondria following DNA damage. In total, this report adds to the body of work outlining the roles of PARP following DNA damage recognition and activation, demonstrating that ADP-ribose metabolism plays an important role in cell death regulation by both direct and indirect means.
Type:
text; Electronic Dissertation
Keywords:
ADP-ribosylation; AIF; Mitochondria; ND1; PARG; PARP
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmaceutical Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Jacobson, Myron K.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleThe Role of ADP-Ribosylation in Mitochondria-Mediated Cell Deathen_US
dc.creatorWhatcott, Clifford Jasonen_US
dc.contributor.authorWhatcott, Clifford Jasonen_US
dc.date.issued2009en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractPoly(ADP)ribose (PAR) metabolism is essential to many cellular functions, including the maintenance of genomic integrity, the regulation of cell death mechanisms, as well as the regulation of gene expression. Recent work has uncovered many new players in the expanding effort to understand PAR metabolism and its cellular impact. PARP-1, the prototypical poly(ADP)ribose polymerase, was the first to be discovered, and has since been shown to be vital in the cellular response to DNA damage. Indeed, one report demonstrating that PARP-1 activation is required for apoptosis-inducing factor (AIF) release from mitochondria uncovered a novel link between DNA damage and signaling for cell death. The events following PARP activation, leading to signaling for AIF release, however, are still poorly understood. Based on our observations, we have developed a model to explain the nuclear/mitochondrial crosstalk that occurs following PARP activation. The work presented here answers several important questions regarding the relationship between ADP-ribose metabolism and mitochondria, including the role of PAR in signaling for the release of AIF, the presence of ADP-ribose metabolism protein members in mitochondria, and mitochondrial transcriptional effects following PARP activation. This work presents several novel findings, including the first report of a mitochondrial matrix isoform of poly(ADP-ribose) glycohydrolase (PARG) as well as direct evidence of mitochondria-associated PARP activity. Furthermore, it provides evidence for a novel effect of PARP-1 activation, in the specific transcriptional upregulation of the mitochondrial gene, NADH dehydrogenase, subunit 1 (ND1). Our data is consistent with the hypothesis that uncontrolled PARP activity results in energy metabolism dysfunction and cell death. Furthermore, it supports a model in which PARP activity is required for normal transcriptional responses in mitochondria following DNA damage. In total, this report adds to the body of work outlining the roles of PARP following DNA damage recognition and activation, demonstrating that ADP-ribose metabolism plays an important role in cell death regulation by both direct and indirect means.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectADP-ribosylationen_US
dc.subjectAIFen_US
dc.subjectMitochondriaen_US
dc.subjectND1en_US
dc.subjectPARGen_US
dc.subjectPARPen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorJacobson, Myron K.en_US
dc.contributor.committeememberBriehl, Margareten_US
dc.contributor.committeememberGhosh, Indraneelen_US
dc.contributor.committeememberHurley, Laurenceen_US
dc.contributor.committeememberMaggiora, Geralden_US
dc.identifier.proquest10428en_US
dc.identifier.oclc659752062en_US
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