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Genetic Instability Upon the Loss of the Tumour Suppressor Folliculin (FLCN)

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Genetic Instability Upon the Loss of the Tumour Suppressor Folliculin (FLCN) Genetic instability upon the loss of the tumour suppressor folliculin (FLCN) Rachel-Ann Russell June 2019 Thesis submitted to Cardiff University in fulfilment of the requirements for the degree of Doctor of Philosophy 1 Declaration This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed…………………………………. (Candidate) Date…………………………………. STATEMENT 1 This thesis is being submitted in partial of the requirements for the degree of …………………………………. (Insert MCh, MD, MPhil, PhD etc., as appropriate) Signed…………………………………. (Candidate) Date …………………………………. STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. Signed…………………………………. (Candidate) Date …………………………………. STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed…………………………………. (Candidate) Date …………………………………. STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loans after expiry of a bar on access previously approved by the Graduate Development Committee. Signed…………………………………. (Candidate) Date …………………………………. i Acknowledgments Firstly, I would like to express my sincere gratitude to my supervisors Dr Andrew Tee and Dr Elaine Dunlop, for their continuous support and guidance throughout my PhD. For their patience, motivation, and immense knowledge. I could not have imagined better advisors and mentors for my studies. A special thanks goes out to all down at Tenovus Cancer Care for not just providing the funding for the work, but also their friendship and infinite opportunities to engage the public with science. To Mr Jesse Champion and Mr Matthew Lines for whom I partly supervised during their research placements, and whose work I have used to strengthen ideas laid out in this thesis. I am endlessly grateful to my parents, Nigel and Christine Russell, who have provided me with an abundance of moral and emotional support in my life, and whom taught me the value of hard work through their actions. And finally, to the greatest friend I’ll ever have, my husband. Daniel Jones, you are myF everything. Thank you for believing in me when I couldn’t believe in myself. ii Summary Folliculin (FLCN) is a tumour suppressor protein with unclear cellular function. Inactivating germline mutations in FLCN lead to Birt-Hogg-Dubé (BHD) syndrome. BHD patients have an increased risk of developing renal cell carcinoma (RCC). Unlike other genetic disorders with a predisposition to RCC, BHD patients are prone to all tumour subtypes (Khoo et al. 2003; Hudon et al. 2010). FLCN acts as a classical tumour suppressor in that a ‘second-hit’, deactivating mutation in the second allele, is required for cellular transformation. FLCN has been implicated in numerous signalling pathways and cellular processes. Most notably it is involved in mTOR, AMPK and HIF signalling, mitochondrial biogenesis, autophagy and membrane trafficking (Klomp et al. 2010; Tee and Pause 2013; Dunlop et al. 2014; Yan et al. 2016a). Despite this breadth of function, its currently unclear how FLCN loss contributes to the development of RCC. Therefore, to better define the tumour suppressor role of FLCN a protein-protein interaction assay, using FLCN as bait, was carried out. This revealed that FLCN interacts with numerous proteins involved in DNA-damage response and/or cell cycle regulation. To explore this further, RNAi was used to generate FLCN knockdown in human proximal tubule kidney cells. In this study, FLCN was demonstrated to interact with DNA- dependent protein kinase catalytic subunit (DNA-PKcs); the apical protein in non- homologous end joining repair (NHEJ) of double strand DNA breaks (DSB). The association of FLCN with DNA-PKcs was shown to weaken when cells are subjected to DNA damage (via ionising radiation). As a direct consequence of FLCN knockdown evidence suggest kidney cells accumulate double-strand DNA damage. Furthermore, FLCN-deficient cells display perturbed G1/S checkpoint and it is thought these cells prematurely commit to cellular division. Ultimately, this thesis highlights a novel role of FLCN within renal cell tumorigenesis and suggests it could function to maintain genomic stability. Our basic understanding of RCC within the general population is limited. Nevertheless, genetic conditions (such as BHD) that predispose individuals to cancer, provide valuable insights into somatic tumour development. By using BHD syndrome as a model of genetic instability, further work should focus on mechanistically establishing FLCN’s role in genomic integrity and will provide valuable insight into sporadic renal cancer within the general population. iii Abbreviations ABC lymphoma Activated B-cell ACC Acetyl-CoA carboxylase AEC Alveolar epithelial cells AICAR 5-Aminoimidazole-4-carboxamide ribonucleotide AMPK 5' AMP-activated protein kinase APBB1 Amyloid beta A4 precursor protein-binding family B member 1 ATM Ataxia telangiectasia mutated ATP Adenosine triphosphate ATR Ataxia telangiectasia and Rad3 related BC Betweenness centrality BER Base excision repair BHD Birt-Hogg-Dube BRCA1 Breast Cancer Type 1 Susceptibility Protein BRCA2 Breast Cancer Type 2 Susceptibility Protein BrdU 5-bromo-2'-deoxyuridine BSA Bovine serum albumin C.elegans Caenorhabditis elegans CC Closeness centrality CDK Cyclin-dependent kinases cDNA Copy deoxyribonucleic acid Chk1 Checkpoint kinase 1 Chk2 Checkpoint kinase 2 CT computerized tomography CYP1A1 cytochrome P4501A1 dBHD Drosophila melanogaster homolgue of folliculin ddH2O Double distilled water DDR DNA damage response DEGs Differentailly expressed genes DENN differentially expressed in neoplastic versus normal cells protien domain DNA-PKcs DNA-dependent protein kinase catalytic subunit DSB Double-strand DNA breaks dsDNA Double-strand DNA DTT Dithiothreitol EdU 5-ethynyl-2´-deoxyuridine EGFR Epidermal growth factor receptor eIF4E Eukaryotic translation initiation factor 4E FDR False discovery rate FLCN Folliculin Flcn-1 (OK975) flcn deficient Caenorhabditis elegans model FNIP1 Folliculin interacting protien 1 FNIP2 Folliculin interacting protien 2 GABARAP Gamma-aminobutyric acid receptor-associated protein GAP GTPase-activating proteins iv GCB lymphoma Germinal center B-cell GEF Guanine nucleotide exchange factors GG-NER Global genomic -nucleotide excision repair GO-BP Gene ontology cellular component GO-CC Gene ontology biological processes GPNMB Transmembrane glycoprotein NMB GSEA Gene set enrichment analysis GST Glutathione S-transferases HBE Human bronchial epithelial HCC1937 Breast epithelial cell line HEK293 Human embryoic kideny cells 293 HeLa cells Cervical carcinoma cell line HIF Hypoxia-inducible factor His3 Histone 3 HK2 Human proximal tubule 2 cells HOCT hybrid oncocytic/chromophobe tumor HOX homeobox genes HP High passage HR Homologous recombination HRP Horseraddish peroxidase HSP90α Heat-shock protein 90 alpha IMCD-3 Murine inner medullary collecting duct cells Indel Insertion deletion IPA Ingenuity Pathway Analysis IR Ionising radiation k Degree KD Knockdown KIF3A Kinesin-like protein LC-MS/MS Liquid chromatography–mass spectrometry / mass spectrometry LDHA Lactose dehydrogenase Lig IV DNA ligase IV LKB1 Liver kinase B1 LP Low passage MDM2 Mouse double minute 2 homolog MEFs Mouse embryonic fibroblasts MMR Mis-match repair MRI Magnetic resonance imaging mTOR Mechanistic target of rapamycin mTORC1 Mechanistic target of rapamycin complex 1 mTORC2 Mechanistic target of rapamycin complex 2 NaCl Sosium chloride NER Nucleotide excision repair NHEJ Non-homologue end joining NRF1 Nuclear Respiratory Factor 1 NRF2 Nuclear Respiratory Factor 2 PALB2 Partner and localizer of BRCA2 v PARP1 Poly [ADP-ribose] polymerase 1 PBS Phosphate buffered saline PCC Pearson's correlation coefficient PCNA Proliferating cell nuclear antigen PCR Polymerase chain reaction PGC1α Peroxisome proliferator activated receptor gamma coactivator 1 alpha PLCB1 Phospholipase C Beta 1 PP2A Protein phosphatase 2 PPI Protein-protein interaction PVDF Polyvinylidene fluoride qPCR quantitative polymerase chain reaction Rb Retinoblastoma protein RIF1 Telomere-associated protein RIF1 RNA-Seq RNA sequencing ROS Reactive oxygen speices RPA1 Replication Protein A1 RPA2 Replication Protein A2 Rpt4 26S proteasome subunit RPT4 S.pombe Schizosaccharomyces pombe SDS-PAGE sodium dodecyl sulfate–polyacrylamide gel electrophoresis shRNA short hairpin RNA siRNA small interfering RNA SNP Single-nucleotide polymorphism SP1 Transcription Factor Sp1 SQSTM1/p62 Sequestosome-1 SSBs Single-strand breaks TAMs Tumour associated macrophage TBST Tris-buffered saline tween TC-NER Transcription-coupled nucleotide excision repair TFAM transcription factor A, mitochondrial TGFA Transforming Growth Factor Alpha TSC1 Tuberous Sclerosis 2 Protein TSC2 Tuberous Sclerosis 1 Protein ULK1 Unc-51 Like Autophagy Activating Kinase 1 UV Ultraviolet index VHL Von Hippel-Lindau WT Wild type XLF XRCC4-like factor XPO1 Exportin 1 XRCC4 X-ray repair cross-complementing protein 4 vi Table of Content Declaration ................................................................................................................................... i Acknowledgments ......................................................................................................................
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