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

Carroll, Kathryn Anne (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/r781wg79r?locale=it
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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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