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A Genome-Wide Study of Homologous Recombination in Mammalian Cells Identifies RBMX, a Novel Component of the DNA Damage Response

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A Genome-Wide Study of Homologous Recombination in Mammalian Cells Identifies RBMX, a Novel Component of the DNA Damage Response A Genome-Wide Study of Homologous Recombination in Mammalian Cells Identifies RBMX, a Novel Component of the DNA Damage Response The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Adamson, Brittany Susan. 2012. A Genome-Wide Study of Homologous Recombination in Mammalian Cells Identifies RBMX, a Novel Component of the DNA Damage Response. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:10448771 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA © 2012 – Brittany Susan Adamson All rights reserved. Dissertation Advisor: Dr. Stephen J. Elledge Brittany Susan Adamson A genome-wide study of homologous recombination in mammalian cells identifies RBMX, a novel component of the DNA damage response Abstract Repair of DNA double-strand breaks is critical to the maintenance of genomic stability, and failure to repair these DNA lesions can cause loss of chromosome telomeric regions, complex translocations, or cell death. In humans this can lead to severe developmental abnormalities and cancer. A central pathway for double-strand break repair is homologous recombination (HR), a mechanism that operates during the S and G2 phases of the cell cycle and primarily utilizes the replicated sister chromatid as a template for repair. Most knowledge of HR is derived from work carried out in prokaryotic and eukaryotic model organisms. To probe the HR pathway in human cells, we performed a genome-wide siRNA-based screen; and through this screen, we uncovered cellular functions required for HR and identified proteins that localize to sites of DNA damage. Among positive regulators of HR, we identified networks of pre-mRNA-processing factors and canonical DNA damage response effectors. Within the former, we found RBMX, a heterogeneous nuclear ribonucleoprotein (hnRNP) that associates with the spliceosome, binds RNA, and influences alternative splicing. We found that RBMX is required for cellular resistance to genotoxic stress, accumulates at sites of DNA damage in a poly(ADP-ribose) polymerase 1-dependent manner and through multiple domains, and promotes HR by facilitating proper BRCA2 expression. Screen data also revealed that the mammalian recombinase RAD51 is commonly off-targeted by siRNAs, presenting a cautionary note to those studying HR with RNAi and highlighting the vulnerability of RNAi screens to off-target effects in general. Candidate validation through secondary screening with independent reagents successfully circumvented the effects of off-targeting and set a new standard for reagent redundancy in RNAi screens. iii PREFACE TABLE OF CONTENTS FIGURES.................................................................................................................................................... vi TABLES..................................................................................................................................................... vii SUPPLEMENTARY TABLES................................................................................................................ vii COMMON ABBREVIATIONS..............................................................................................................viii ACKNOWLEDGEMENTS....................................................................................................................... ix Chapter One: Introduction ........................................................................................................................ 1 I. DNA damage....................................................................................................................................... 2 1-1. The DNA molecule..................................................................................................................... 2 1-2. DNA lesions and repair pathways............................................................................................... 3 1-3. Medical rationale for the study of DNA repair........................................................................... 6 II. The vertebrate DNA damage response (DDR)............................................................................... 7 2-1. Signaling and checkpoint activation ........................................................................................... 7 2-2. Visualization of the DNA damage response by immunofluorescence techniques ................... 12 III. Mechanisms of DNA repair.......................................................................................................... 14 3-1. Single-strand break repair (SSBR) and the role of PARP ........................................................ 14 3-2. Double-strand break repair: Non-homologous end-joining (NHEJ) ........................................ 16 3-2-1. Canonical non-homologous end-joining (c-NHEJ) ........................................................ 16 3-2-2. Alternative non-homologous end-joining (a-NHEJ) and microhomology-mediated end- joining (MMEJ) .......................................................................................................................... 18 3-3. Double-strand break repair: homologous recombination (HR) ................................................ 19 3-3-1. A Historical Perspective.................................................................................................. 19 3-3-2. Models of homologous recombination ........................................................................... 23 3-3-3. Presynapsis: Resection.................................................................................................... 23 3-3-4. Presynapsis: Formation of the RAD51 nucleoprotein filament...................................... 29 3-3-5. Presynapsis: Mediators of the RAD51 nucleoprotein filament ...................................... 31 3-3-6. Synapsis .......................................................................................................................... 35 3-3-7. Postsynapsis: Formation, resolution and dissolution of DNA intermediate structures... 37 3-3-8. The role of BRCA1......................................................................................................... 42 3-4. Double-strand break repair: Single-strand annealing (SSA) .................................................... 46 3-5. Double-strand break repair: Regulation of pathway choice ..................................................... 46 Chapter Two: A genetic screen for regulators of mammalian homologous recombination.............. 49 I. Introduction...................................................................................................................................... 50 1-1. Screen Rationale ....................................................................................................................... 50 1-2. RNAi-mediated gene silencing and genome-wide RNAi screening technologies ................... 52 II. Results.............................................................................................................................................. 53 2-1. A genome-wide siRNA screen to identify regulators of homologous recombination.............. 53 2-2. Identification and validation of candidate HR regulators......................................................... 55 2-3. Network analysis....................................................................................................................... 60 III. Discussion....................................................................................................................................... 63 IV. Materials and Methods ................................................................................................................. 67 4-1. Cell culture................................................................................................................................ 67 4-2. High-throughput (HTP) screening ............................................................................................ 67 4-3. Candidate selection ................................................................................................................... 68 iv PREFACE Chapter Three: RAD51 is a predominantly off-targeted transcript in mammalian cells .................. 71 I. Introduction...................................................................................................................................... 72 1-1. Common caveats to genetic studies using RNAi...................................................................... 72 1-2. Endogenous mircoRNAs .......................................................................................................... 73 1-3. Sequence-based targeting of the endogenous RNAi machinery............................................... 74 1-4. Predictable sequence-based off-targeting ................................................................................. 75 II. Results.............................................................................................................................................. 75 2-1. Three candidate HR regulators localize to sites of DNA damage: HIRIP3, RBMX, DDX17 . 75 2-2. Off-target RAD51 depletion contributes to screen false positives ...........................................
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