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Phd Thesis Antonina Zappone.Pdf Abstract ABSTRACT In vertebrates, the UUAGGG telomere repeat containing long non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres resulting the formation of R-loop structures, replicative stress and telomere instability. RNA:DNA hybrids represent a threat to genomic stability, but also contribute to recombination based alternative lengthening of telomeres (ALT). My PhD thesis aimed to identifie novel TERRA interactors involved in regulation of RNA:DNA hybrids (project 1) and to obtain new insights into the molecular function of TERRA interactrors in telomere regulation by identifying novel proteins (project 2). Here, we identify the TERRA binding proteins SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. SFPQ acts as a barrier for homologous recombination at telomeres, thereby impacting on telomere length homeostasis. Our data identifies the RNA binding proteins SFPQ as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids. Because of lack of enzymatic activity in SFPQ, we performed a mass spectrometry analysis and we found DAXX as novel SFPQ interacting protein. After the identification od SFPQ interacting domain with DAXX, we carried out preliminary experiment to evaluate the role od DAXX in DNA damage activation, in induction of replication defects and telomere dysfunction. I Index 1. INTRODUCTION ................................................................................................ 1 1.1 Telomeres ............................................................................................................................... 1 Telomere structure and functions ................................................................................................................ 1 The Shelterin complex protects telomeres from signalling DNA damage .................................................... 2 1.2 Regulation of telomere maintenance ....................................................................................... 5 Replicative senescence ................................................................................................................................. 6 Telomere length maintenance by telomerase .............................................................................................. 6 1.2.2.1 Alternative Lengthening of Telomeres ................................................................................................. 9 1.2.2.2 Alternative Lengthening of Telomeres mechanism ........................................................................... 10 1.3 The DNA damage repair at telomeres .................................................................................... 13 Non-homologous end joining (NHEJ) .......................................................................................................... 13 Homology-Directed Repair (HDR) ............................................................................................................... 14 1.3.2.1 T-loop homologous recombination (T-loop HR) ................................................................................ 14 1.3.2.2 Telomeric sister chromatid exchange (T-SCE) .................................................................................... 15 1.3.2.3 Homologous recombination with interstitial sites ............................................................................. 16 1.4 Physiological relevance of RNA:DNA by hybrids ..................................................................... 16 R-Loops formation and functions ............................................................................................................... 16 Physiological roles of RNA:DNA hybrids ..................................................................................................... 17 Molecular factors involved in R-Loops Formation ...................................................................................... 17 R-Loop and DNA Damage ............................................................................................................................ 18 1.5 Complex nucleic structures formed at telomere ..................................................................... 19 Telomere repeat containing RNA and R-loops at telomeres ...................................................................... 19 TERRA and telomeric R-Loop formation ..................................................................................................... 21 2. AIM OF THE THESIS ........................................................................................ 23 3. MATERIALS AND METHODS ........................................................................... 24 3.1 Cell lines and culture ............................................................................................................. 24 3.2 siRNA and plasmids transient transfection ............................................................................. 24 3.3 Retroviral transduction of human cells ................................................................................... 24 3.4 Generation of SFPQ mutants.................................................................................................. 25 3.5 Protein extracts and Western blotting.................................................................................... 25 3.6 Immunofluorescence ............................................................................................................. 26 II Index 3.7 Interphase Telomere Q-FISH .................................................................................................. 26 3.8 Immunofluorescence combined with RNA FISH ...................................................................... 27 3.9 Chromosome Orientation FISH (CO-FISH) ............................................................................... 27 3.10 ChIP assay and telomere dot-blots ......................................................................................... 28 3.11 Mass-spectrometry analysis................................................................................................... 28 3.12 Northern blot ........................................................................................................................ 30 3.13 DNA:RNA immunoprecipitation (DRIP) ................................................................................... 30 3.14 Antibodies table .................................................................................................................... 31 4. RESULTS ......................................................................................................... 32 4.1 Project 1: Identification of novel TERRA interactors that control mammalian telomeres .......... 32 Novel TERRA interaction proteins ............................................................................................................... 32 SFPQ and NONO structure and functions ................................................................................................... 33 4.1.2.1 SFPQ and NONO structure ................................................................................................................. 33 4.1.2.2 Role os SFPQ and NONO in RNA metabolism, transcription regulation and DNA repair ................... 34 SFPQ and NONO localize to telomere ......................................................................................................... 36 SFPQ suppress TERRA accumulation at telomere preventing the formation of RNA:DNA hybrids ............ 38 4.1.4.1 SFPQ control TERRA abundance at telomeres ................................................................................... 38 4.1.4.2 SFPQ prevent RNA:DNA hybrid formation at telomeres .................................................................... 39 Loss of SFPQ causes replication defects at telomeres ................................................................................ 43 LOSS of SFPQ regulate telomere fragility and homologous recombination at telomere ........................... 45 4.1.6.1 Fragility ............................................................................................................................................... 45 4.1.6.2 SFPQ suppress recombination at telomeres ...................................................................................... 47 SFPQ regulate telomere length homeostasis in telomerase negative cancer cells .................................... 49 Working model ........................................................................................................................................... 50 4.2 Project 2: Identification of novel SFPQ interactors .................................................................. 52 SFPQ interaction with the histone chaperone DAXX .................................................................................. 52 4.2.1.1 Identification os SFPQ interacting protein ......................................................................................... 52 Protein-protein network analysis ............................................................................................................... 53 Validation of SFPQ-DAXX interaction .........................................................................................................
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