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BRCA1 Localization to the Telomere and Its Loss from the Telomere In BRCA1 LOCALIZATION TO THE TELOMERE AND ITS LOSS UPON DNA DAMAGE A Dissertation Submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry and Molecular & Cellular Biology By Rahul D. Ballal, M.S. Washington, DC February 4, 2010 Copyright 2010 by Rahul D. Ballal All Rights Reserved ii BRCA1 LOCALIZATION TO THE TELOMERE AND ITS LOSS UPON DNA DAMAGE Rahul D. Ballal, MS Mentor: Eliot M. Rosen, MD, PhD ABSTRACT BRCA1, a tumor suppressor, participates in DNA damage signaling and repair. Previously, we showed that BRCA1 over-expression caused inhibition of telomerase activity and telomere shortening in breast and prostate cancer cells. We now report that BRCA1 knockdown causes increased telomerase reverse transcriptase (TERT) expression, telomerase activity, and telomere length. Studies utilizing a combination of BRCA1 and TERT siRNAs suggest that BRCA1 also regulates telomere length independently of telomerase. Using telomeric ChIP assays, we detected BRCA1 at the telomere and demonstrated time-dependent loss of BRCA1 from the telomere following DNA damage. Further studies suggest that BRCA1 interacts with TRF1 and TRF2 in a DNA-dependent manner and that some of the nuclear BRCA1 colocalizes with TRF1/2. Our findings further suggest that Rad50 is required to localize BRCA1 at the telomere and that the association of BRCA1 with Rad50 does not require DNA. Finally, we found that BRCA1 regulates the length of the 3’ G-rich overhang in a manner that is dependent upon Rad50. Our findings suggest that BRCA1 is recruited to the telomere in a Rad-50- dependent manner and that BRCA1 may regulate telomere length and stability through its presence at the telomere. iii ACKNOWLEDGEMENTS I would like to thank Dr. Eliot Rosen who served as my mentor throughout my PhD. I am grateful for his scientific acumen, the intellectual freedom he allowed, and most importantly for his mentorship. I would also like to thank my committee members, Dr. Partha Banerjee (chair), Dr. Albert Fornace Jr., and Dr. Vicente Notario. Each one of them has enriched my education, contributed to this work, and supported me through the challenges of life and science. From the Rosen Lab I would like to thank Dr. Tapas Saha for teaching me early in my scientific career and Dr. Jingwen Xu, who always kept me grounded in reason. I would also like to thank the Biochemistry department and program for supporting my career. Finally, I would like to thank the Broad Institute of MIT/Harvard for allowing me to continue my scientific pursuits. I would like to thank my Georgetown friends who helped me get through the PhD: Julie, Daniel, Laurent, Geoffrey, Caitlin, Pete (Johnson), Malena, and Tabari. I would also like to thank my family. From my parents and sister to my in-laws and sister- in-law, you have truly made this project possible. Without you, I would have not been able to complete this work. Finally, to my wife Sonia who is my dream, redemption, and savior; I love you. To my amazingly talented Meenu, I hope to inspire you as many have inspired me. iv DEDICATION This dissertation is dedicated to my wife Sonia and daughter Sameena. I love you both. v LIST OF ABBREVIATIONS Chapter I BRCA1-breast cancer susceptibility gene 1 BASC-BRCA1 associated genome complex ATM-ataxia telangiectasia, mutated protein kinase ATR- ATM and Rad3-related protein kinase CHk2-checkpoint homolog 2 DDR-DNA damage response DSB-double strand break BARD1-BRCA1 associated RING domain 1 MRN Complex-Mre11-Rad50-Nbs1 NLS-nuclear localization signal Ser-Serine RNA Pol II-RNA polymerase II CStF-50-cleavage stimulation factor CtIP-C-terminal binding protein-interacting protein TRF1/2-telomere repeat binding factors 1/2 PARP-poly-(ADP-ribose)-polymerase Tankyrase-TRF1 interacting ankryin-related poly-(ADP-ribose)-polymerase TIN2-TRF1 interacting nuclear protein 2 NHEJ-non-homologous end joining HR-homologous recombination POT1-protector of telomeres 1 TPE-telomere position effect TERT-telomerase reverse transcriptase TR-telomerase RNA component ALT-alternative lengthening of telomeres PML-promyelocyctic leukemia DNA-PK-DNA protein kinase Chapter II TPG-total product generated (telomerase assay) siRNA-small interfering RNA RT-PCR-reverse transcriptase polymerase chain reaction Q-PCR-quantitative polymerase chain reaction TRF-telomere repeat fragment (telomere length assay) SEM-standard error of mean vi Chapter III ADR-adriamycin CDDP-cis-diaminodichloroplatinum (cis-platinum) ChIP-chromatin immunoprecipitation FISH-fluorescence in situ hybridization IP-immunoprecipitation IgG-immunoglobulin G Chapter IV HPA-hybridization protection assay DSN-double strand nuclease assay AE-Acridinium Ester Chapter V SWI/SNF-switch sucrose non-fermentable (yeast nucleosome) T-loop HR-telomere loop homologous recombination vii TABLE OF CONTENTS Chapter I 1.A. Introduction 1 1.B. BRCA1: Structure & Function 5 1.C. Telomere Machinery: Structure & Function 14 1.D. Telomere Machinery: Cancer & DNA Repair 24 1.E. Statement of Purpose 30 1.F. Figure Legends 33 1.G. Figures 36 Chapter II 47 2.A. Abstract 48 2.B. Materials & Methods 49 2.C. Results 53 2.D. Discussion 55 2.E. Acknowledgements 58 2.F. Figure Legends 59 2.G. Figures 62 Chapter III 68 3.A. Abstract 69 3.B. Materials & Methods 70 3.C. Results 76 3.D. Discussion 83 3.E. Acknowledgements 88 3.F. Figure Legends 89 3.G. Figures 98 Chapter IV 115 4.A. Abstract 116 4.B. Materials & Methods 117 4.C. Results 119 4.D. Discussion 122 4.E. Acknowledgements 125 4.F. Figure Legends 126 4.G. Figures 130 Chapter V 136 5.A. Conclusions & Future Studies 137 References 144 viii LIST OF FIGURES Chapter I Figure 1: BRCA1 Functional Domains and Selected Binding Partners 36 Figure 2: BRCA1 Functionality and Network 37 Figure 3: Model for BRCA1 mediated DNA Repair 38 Figure 4: Function of BRCA1 in Cell Cycle Checkpoints 39 Figure 5: Proposed Lariat Structure of Telomere (T-loop/D-Loop) 40 Figure 6: Telomeres Switch between Open and Closed Conformations 41 Figure 7: Main Components of the Shelterin Complex and their Binding Partners 42 Figure 8: Model for G-strand Overhang Creation 43 Figure 9: Model for Telomere Elongation by Telomerase 44 Figure 10. The Telomeric Cancer Hypothesis 45 Figure 11. DDR proteins localizes to the Telomere 46 Chapter II Figure 12: BRCA1 knockdown causes increased expression of the human telomerase reverse transcriptase (hTERT) 62 Figure 13:BRCA1 knockdown does not alter expression of TRF1, TRF2, hTR, or POT1 in T47D cells 63 Figure 13G: BRCA1 knockdown does not alter expression of TRF1, TRF2, or hTR in MCF-7 cells. 64 Figure 14: BRCA1 knockdown causes an increase in telomerase activity 65 Figure 15:BRCA1 knockdown causes telomere lengthening 66 Chapter III Figure 16: Telomeric chromatin immunoprecipitation (ChIP) assays to detect BRCA1 protein at the telomere in T47D cells 98 Figure 16G. Telomeric chromatin immunoprecipitation (ChIP)assays to detect BRCA1 protein at the telomere in MCF-7 cells 99 Figure 17: Adriamycin (ADR) and cis-platinum (CDDP) cause loss of BRCA1 from the telomere in T47D cells 100 Figure 17G: Adriamycin (ADR) and Cis-platinum (CDDP) cause loss of BRCA1 from the telomere in MCF-7 cells 101 Figure 18: BRCA1 reappears at the telomere following washout of ADR 102 Figure 18G: Adriamycin (ADR) treatment does not alter hTERT expression 103 Figure 19: Knockdown of the telomeric repeat binding protein TRF1 or TRF2 causes loss of BRCA1 from the telomere in T47D cells 104 ix Figure 19G: Knockdown of the telomeric repeat binding protein TRF1 or TRF2 causes loss of BRCA1 from the telomere in MCF-7 cells 105 Figure 20: Knockdown of BRCA1 does not cause loss of TRF1 or TRF2 from the telomere 106 Figure 20G: BRCA1 associates with TRF1 and TRF2 in vivo 107 Figure 21: BRCA1 association with TRF1 and TRF2 is mediated by DNA 108 Figure 21G: BRCA1 association with TRF1 is disrupted by treatment with Bal-31 109 Figure 22: Colocalization of BRCA1 with TRF1 and TRF2 in T47D cells 110 Figure 22G: Knockdown of BRCA1, TRF1, or TRF2 reduces protein expression 111 Figure 23: Teli-FISH of BRCA1 colocalization with telomeric probe in T47D cells 112 Figure 23G: Colocalization of BRCA1 with TRF1 and TRF2 in MCF-7 cells 113 Figure 23H: Teli-FISH analysis shows BRCA1 co-localizes with the Telomere in MCF-7 cells. 114 Chapter IV Figure 24: BRCA1-siRNA blocks telomere shortening due to TERT knockdown 130 Figure 25: Rad50 knockdown causes loss of telomeric BRCA1 in T47D cells 131 Figure 25G: BRCA1 association with Rad50 does not require DNA 132 Figure 26: BRCA1 regulates 3’ G-strand overhang length: hybridization protection assay 133 Figure 26G: ADR exposure for up to 72 hr causes little or no change in telomere length 134 Figure 27: BRCA1 regulates G-strand overhang length: double-strand nuclease (DSN) assays 135 x CHAPTER I xi 1.A INTRODUCTION Breast cancer ranks as the number one cause of cancer incidence and the second leading cause of cancer mortality among women (16,78,119). Approximately 5-10% of breast cancer incidence is based on the inheritance of mutations in cancer susceptibility genes (87). It is estimated that approximately half of the hereditary breast cancer cases are due to mutations in Breast Cancer Gene 1 (BRCA1). Carriers of the BRCA1 mutation have a significantly increased chance (50-80%) of developing breast cancer by the age of 70, as well as an elevated risk to develop ovarian cancer (~40%) by the same age (31,36). While hereditary cases make up a small fraction of total breast cancer incidence, a large proportion of sporadic breast cancers (~60%) show decreased or absent BRCA1 expression (67).
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