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TELOMERE DYSFUNCTION IN HUMAN DISEASES: FUNCTIONAL CHARACTERIZATION OF TELOMERASE GENE MUTATIONS AND OF TELOMERE-ASSOCIATED GENE EXPRESSION REGULATION

Carroll, Kathryn Anne (2011)
Dissertation (142 pages)
Committee Chair / Thesis Adviser: Ly, Hinh
Committee Members: Benian, Guy ; Fridovich-Keil, Judith ; Liang, Yuying ; Saavedra, Harold
Research Fields: Biology, Molecular; Biology, Genetics
Keywords: Telomere; Telomerase; Bone Marrow Failure Syndromes; hTERT; hTERC; hTR; TIN2
Program: Laney Graduate School, Biological and Biomedical Sciences (Genetics and Molecular Biology)
Permanent url: http://pid.emory.edu/ark:/25593/926j8

Abstract

It has been over one hundred years since the first reported case of dyskeratosis congenita
(DC) and over twenty since the discovery of telomerase, an enzyme that adds telomeric
DNA repeats to chromosome ends. Emerging evidence suggests that telomere
dysfunction plays an important role in the pathogenesis of DC and other human disorders
involving tissues that require rapid repair and renewal capacities. However, we still do
not fully understand how mutations in telomere maintenance genes contribute to disease
development in affected individuals. We have identified and characterized a number of
telomerase mutations found in patients with DC, aplastic anemia (AA), myelodysplastic
syndromes (MDS), idiopathic pulmonary fibrosis (IPF), and acute myeloid leukemia
(AML). These studies have revealed important domains/residues of the telomerase
reverse transcriptase hTERT protein and of its intrinsic hTERC RNA template required
for optimal enzymatic function. We have also investigated the effects of patient-
associated sequence changes in the proximal promoter region of the hTERC gene and
explored the possible regulatory mechanism of expression of the telomere-associated
protein TIN2. Collectively, these studies offer important insights into the molecular
mechanisms of telomere maintenance under normal and pathological conditions in
humans.

Table of Contents

CHAPTER 1: INTRODUCTION 1

1.1 Human Telomerase Basics 1
1.2 Mammalian Telomere Structure and the Shelterin Complex 2
1.3 Telomere Maintenance in Other Organisms 3
1.4 Telomerase and Disease 9
1.5 Telomerase Mutations in Human Blood Disorders 10
1.6 Telomerase Mutations in Non-Hematological Disorders 18
1.7 Mouse Models of Dyskeratosis Congenita 20
1.8 Conclusions 24
Figures 26
CHAPTER 2:
2.1 Identification and Functional Characterization of Novel
Telomerase Variant Alleles in Japanese Patients with Bone-Marrow
Failure Syndromes
31
Abstract 32
Introduction 33
Materials and Methods 34
Results 38
Discussion 42
Tables 45
Figures 48
Figure Legends 50
2.2 Functional Characterization of Telomerase Sequence Variants
Identified in Patients with Short Telomeres
52
Introduction 53
Materials and Methods 54
Results 56
Discussion 61
Tables 62
Figures 63
Figure Legends 74
CHAPTER 3: TRANSCRIPTIONAL ACTIVATION OF TINF2, A
GENE ENCODING THE TELOMERE-ASSOCIATED PROTEIN TIN2,
BY SP1 and NF-κB FACTORS 79
Abstract 80
Introduction 81
Materials and Methods 83
Results 90
Discussion 98
Figures 101
Figure Legends 106
CHAPTER 4: DISCUSSION 110

REFERENCES 117

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