Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: telomerase activity; telomere lengths; hematopoietic stem cells. Includes bibliographical references (p. 64-71).

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: ependymin; telomerase; telomere Includes bibliographical references. (p.46-49)

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Thesis (Ph.D.)--Brown University, 2005. / Vita. Thesis advisor: John M. Sedivy. Includes bibliographical references (leaves 135-172). Also available online.

Suen, Wai Chiu. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 117-128). / Abstract also in Chinese. / ACKNOWLEDGEMENTS --- p.ii / LIST OF ABBREVIATIONS --- p.iii / ABSTRACT --- p.v / 摘要 --- p.vii / LIST OF PUBLICATIONS --- p.viii / TABLE OF CONTENTS --- p.ix / Chapter CHAPTER 1. --- INTRODUCTION --- p.1 / Chapter 1.1. --- Nature of Telomeres / Chapter 1.1.1. --- Telomere structure --- p.1 / Chapter 1.1.2. --- Importance of telomeres --- p.2 / Chapter 1.1.3. --- Telomere length attrition during replicative senescence --- p.3 / Chapter 1.1.4. --- Telomere length maintenance --- p.6 / Chapter 1.1.5. --- "Oxidative stress, inflammatory process and telomere length" --- p.7 / Chapter 1.1.6. --- Telomere attrition rate --- p.8 / Chapter 1.2. --- "Age, Gender and Telomere Length" / Chapter 1.2.1. --- Age and telomere length --- p.10 / Chapter 1.2.2. --- Gender difference of telomere length --- p.10 / Chapter 1.3. --- Health Status and Telomere Length --- p.13 / Chapter 1.3.1. --- Coronary heart diseases --- p.13 / Chapter 1.3.2. --- Cancers --- p.14 / Chapter 1.3.3. --- Infections and chronic inflammation --- p.15 / Chapter 1.3.4. --- Bone mineral density --- p.16 / Chapter 1.3.5. --- Neurodegenerative diseases --- p.17 / Chapter 1.3.6. --- Frailty and mortality --- p.19 / Chapter 1.4. --- "Lifestyles, Environment and Telomere Length" --- p.21 / Chapter 1.4.1. --- Obesity --- p.21 / Chapter 1.4.2. --- Smoking --- p.22 / Chapter 1.4.3. --- Physical activity --- p.23 / Chapter 1.4.4. --- Diet --- p.23 / Chapter 1.4.5. --- Psychological stress --- p.24 / Chapter 1.4.6. --- Socioeconomic status --- p.24 / Chapter 1.5. --- Methods of Measuring Telomere Length --- p.27 / Chapter 1.6. --- Aims and Hypotheses of the Study --- p.31 / Chapter 1.6.1. --- Aims --- p.31 / Chapter 1.6.2. --- Hypotheses --- p.31 / Chapter CHAPTER 2. --- SUBJECTS AND METHODS --- p.33 / Chapter 2.1. --- Subjects Recruitment --- p.34 / Chapter 2.2. --- Interview --- p.34 / Chapter 2.3. --- Anthropometry --- p.35 / Chapter 2.4. --- DNA Extraction and Storage --- p.35 / Chapter 2.5. --- Telomere Length Measurement --- p.37 / Chapter 2.5.1. --- Terminal restriction fragment analysis --- p.37 / Chapter 2.5.2. --- Quantitative real-time PCR --- p.39 / Chapter 2.6. --- Self-perceived Health --- p.46 / Chapter 2.7. --- Medical History --- p.46 / Chapter 2.8. --- Bone Mineral Density --- p.47 / Chapter 2.9. --- Frailty Index --- p.47 / Chapter 2.10. --- Mortality Rate --- p.50 / Chapter 2.11. --- Smoking --- p.50 / Chapter 2.12. --- Physical Activity --- p.51 / Chapter 2.13. --- Dietary Intakes --- p.51 / Chapter 2.15. --- Socioeconomic Status --- p.52 / Chapter 2.16. --- Statistical Analysis --- p.53 / Chapter CHAPTER 3. --- RESULTS AND DISCUSSIONS --- p.55 / Chapter 3.1. --- Demographics --- p.55 / Chapter 3.2. --- Telomere Length Distribution --- p.64 / Chapter 3.2.1. --- Age and telomere length --- p.64 / Chapter 3.2.2. --- Gender and telomere length --- p.68 / Chapter 3.3. --- Health Status and Telomere Length --- p.71 / Chapter 3.3.1. --- Self-perceived health --- p.71 / Chapter 3.3.2 --- History of diseases --- p.74 / Chapter 3.3.3. --- Bone mineral density --- p.80 / Chapter 3.3.4. --- Frailty index --- p.86 / Chapter 3.3.5. --- Mortality rate --- p.91 / Chapter 3.4. --- "Lifestyles, Environment and Telomere Length" --- p.94 / Chapter 3.4.1. --- Smoking --- p.94 / Chapter 3.4.2. --- Physical activity --- p.99 / Chapter 3.4.3. --- Diet --- p.104 / Chapter 3.4.4. --- Socioeconomic status --- p.109 / Chapter CHAPTER 4. --- CONCLUSIONS --- p.115 / Chapter 4.1. --- General conclusions --- p.115 / Chapter 4.2 --- The Significance of telomere length in the elderly --- p.115 / Chapter 4.3. --- Future Works and Prospect --- p.116 / References --- p.117

Telomeres are located at the ends of all eukaryotic chromosomes and provide the stability of chromosomes. They consist of simple tandem hexametric repeats and play an important part in cell longevity. In human lymphocytes, telomeres shorten progressively with age. Mental retardation (MR) is a disorder with intelligence quotient below average (IQ < 70) and impairment in adaptive skills. IQ by Weschsler Adult Intelligence Scales revised (WAIS-R) appears to peak in the of 30-34 and thereafter decline gradually. Life expectancy is defined as the number of years remaining to be lived. The overall increase in life expectancy indicates an improvement in longevity. The life expectancy of MR patients is shorter than that of the general population. The purpose of this study is to predict the relationship between telomere length and IQ in normal control as well as to analyze the differences among the average telomere length for the control and subgroups of MR cases. Fifty-nine patients who met the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for mental retardation were included in this study. According to the degree of intellectual impairment, MR patients were divided into 4 types: mild, moderate, severe, and profound. Fifty-two female nursing students aged 19-21 were recruited as normal controls. DNA was isolated from their lymphocytes. Telomere length was analyzed by Southern blot hybridization. The length was calculated by the Photo CaptMw Version 99.03 software. Correlation between the telomere length and IQ in normal control was performed by the Pearson product-moment correlation. One-way ANOVA was used to test if any differences existed among the normal, mild, moderate, severe, and profound MR. Analyses displayed that there were no correlations between telomere length and IQ including PIQ(r=-0.001; p=0.922), VIQ(r=-0.033; p=0.817), TIQ(r=-0.026, p=0.857), and no difference existed among the normal and subgroups of MR cases. Results obtained from this study indicated that life expectancy of MR patients may approximate to that of the general population if live in the well environment.

Errors in DNA replication can cause chromosome instability and gross chromosomal rearrangements (GCRs). For my thesis work I investigate how chromosome instability can originate in the telomere. Here I report how defects in Cdc13, a telomere specific protein, lead to chromosome instability and GCRs in Saccharomyces cerevisiae. Using a temperature sensitive mutant of Cdc13, I find that cdc13-induced instability can be induced in a single cell cycle and synergizes with replication stress (dNTP depletion via hydroxyurea). Additionally, I find that Cdc13 has to be functional during the cell’s S phase to suppress chromosome instability. Further genetic analysis suggests that that cdc13-induced chromosome instability depends on the generation of single stranded (ss)DNA, but not on the activity of canonical double strand break (DSB) repair pathways such as homologous recombination or non-homologous end joining. Finally, I demonstrate that telomeric unstable chromosomes can later progress and trigger rearrangements at centromeric loci. This system, using the conditional nature of the cdc13 mutation, promises a more complex analysis of the ontogeny of chromosome instability: in this case from errors semi-conservative DNA replication through the telomere to the formation and resolution of unstable chromosomes.

Thesis advisor: Anthony T. Annunziato / The histone acetyltransferase Hat1 is an enzyme that specifically acetylates newly synthesized histone H4 at positions K5 and K12 (or their homologous positions) in all eukaryotes. In Schizosaccharomyces pombe, the deletion of hat1 presents a mutant phenotype. The telomeres in a hat1-del strain become permissive for transcription, as analyzed by a telomeric ura4 marker gene. In this study, we evaluate the efficacy of high copy suppression of this hat1 deletion. Due to high-frequency recombination events in the telomere, it became necessary to create a hat1-rad52 double deletion strain that also contains a telomeric ura4 reporter. High copy suppressor screens for recovery of telomeric silencing yielded several promising transformants. Multiple rounds of testing were performed to assess the recovery of transcriptional repression at the telomere. It was found that despite the anti-recombination effect of deleting rad52, the ura4 reporter was still lost from the telomere through recombination. Additional observation of the hat1-del rad52-del ura4-tel strain revealed a significant synthetic slow-growth phenotype. The double mutant displays a greatly decreased growth rate compared to hat1-del, as well as increased cellular length. Further study showed unique phenotypes on various media, and gene expression studies showed unique patterns of regulation in this double mutant when compared to both a wild- type and its single mutant counterparts (hat1-del, rad52-del). In summary, the telomeric ura4 marker in a hat1-del strain of S. pombe is not stable and is lost by recombination at a high frequency. This has led to the discovery of a double mutant (hat1-del rad52-del) that displays a severe synthetically sick phenotype. / Thesis (MS) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Thesis advisor: Anthony T. Annunziato / Thesis advisor: Charles Hoffman / The Hat1 complex was characterized in <italic>S. pombe</italic>. Through tandem affinity purification and mass spectrometry, it was determined that Hat1 is associated with Mis16 (an orthologue of HAT2). Unlike HAT2 in <italic>S. cerevisiae</italic>, we confirm <italic>mis16</italic> to be an essential gene in <italic>S. pombe</italic>. As expected, the <italic>S. pombe</italic> Hat1 complex was found to acetylate lysines 5 and 12 of histone H4. In contrast to budding yeast, deletion of <italic>hat1</italic> alone resulted in the loss of telomeric silencing without concomitant mutations of the H3 N-terminal domain. Deletion of <italic>hat1</italic> caused an increase of H4 acetylation at telomeres. Additionally, the hyperacetylation of histones also results in the loss of telomeric silencing. Loss of Hat1 did not affect silencing at the inner most repeat (imr) or outer repeat (otr) regions of the centromere, but did appear to increase silencing at the central core region (cnt) of the centromere. The experiments described herein demonstrate Hat1 to be essential for the establishment of proper telomeric silencing in fission yeast, and suggest that the timely acetylation of H4 during chromatin assembly is a unique factor in generating the correct epigenetic state at telomeres in <italic>S. pombe</italic>. Additionally, Hat1 and its acetylation of new H4 may have entirely different roles during telomeric silencing than during silencing at the centromeric central core. Our studies in HeLa cells demonstrated that transcription is involved in the exchange of H2A/H2B in acetylated chromatin regions. The finding that cytosolic H2A can be acetylated at lysine 5 is the first demonstration that cytosolic H2A can be specifically modified <italic>in vivo</italic>. Our results support a model in which H2A/H2B exchange during transcription is mediated by the NAP1 chaperone. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

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