Regulation of Sirtuin-dependent skin cell Senescence by dermatology-associated compounds Alfredo Martínez Gutiérrez ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intelꞏlectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. 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Doctoral Thesis Regulation of Sirtuin-dependent skin cell Senescence by dermatology-associated compounds Universitat de Barcelona Facultat de Medicina Programa de Doctorat en Biomedicina Student Alfredo Martínez Gutiérrez Directors Dr. Alejandro Vaquero García Dra. Josefina Martínez Hoyos Tutor Dr. Manel Esteller Badosa 2 INDEX ACKNOWLEDGEMENTS..................................................................................9 ABBREVIATIONS..............................................................................................11 INTRODUCTION.........................................................................................................13 1. Epigenetic mechanisms................................................................................................13 1.1. DNA methylation.........................................................................................13 1.2. Histone modifications...................................................................................14 1.2.1. Histone acetylation.......................................................................15 1.2.2. Histone methylation......................................................................16 1.2.3. Histone phosphorylation...............................................................16 1.2.4. Histone ubiquitination..................................................................16 1.2.5. Histone sumoylation.....................................................................17 1.2.6. Histone biotinylation....................................................................17 1.3. Non-coding RNAs........................................................................................18 1.3.1. siRNAs.........................................................................................18 1.3.2. miRNAs........................................................................................18 1.3.3. piRNAs.........................................................................................18 1.3.4. lncRNAs.......................................................................................18 2. Sirtuins.........................................................................................................................20 2.1. General introduction of Sirtuins...................................................................20 2.2. SIRT1...........................................................................................................23 2.2.1. Chromatin organization................................................................23 2.2.2. Metabolism...................................................................................23 2.2.3. Autophagy....................................................................................24 2.2.4. Inflammation................................................................................25 2.2.5. Stress response.............................................................................25 2.2.6. DNA repair...................................................................................26 2.2.7. Circadian clock.............................................................................26 2.2.8. SIRT1 and disease........................................................................26 2.3. SIRT2...........................................................................................................27 2.3.1. Chromatin organization................................................................27 2.3.2. Stress response..............................................................................27 2.3.3. Metabolism...................................................................................28 2.3.4. Inflammation................................................................................28 2.3.5. Structural proteins........................................................................28 2.3.6. SIRT2 and disease........................................................................28 2.4. SIRT6...........................................................................................................29 2.4.1. Chromatin organization................................................................29 2.4.2. DNA repair...................................................................................29 2.4.3. Metabolism...................................................................................30 2.4.4. Inflammation................................................................................30 2.4.5. SIRT6 and disease........................................................................30 2.5. SIRT7...........................................................................................................31 2.5.1. Chromatin organization................................................................31 2.5.2. Stress response..............................................................................31 2.5.3. Metabolism...................................................................................32 2.5.4. RNA regulation and ribosome metabolism..................................32 2.5.5. Mitochondria homeostasis............................................................32 2.5.6. DNA repair...................................................................................32 2.5.7. SIRT7 and disease........................................................................32 3 2.6. Role of sirtuins in skin..................................................................................33 2.7. Regulation of sirtuins at different levels.......................................................34 2.7.1. Sirtuin gene expression and post-transcriptional regulation.........34 2.7.2. Post-translational regulation.........................................................35 2.7.3. Complex formation and substrate-dependent regulation..............36 2.8. Sirtuin activators...........................................................................................37 2.9. Sirtuin inhibitors...........................................................................................38 2.10. Role of sirtuins in senescence.....................................................................39 2.10.1. SIRT1..........................................................................................39 2.10.2. SIRT2..........................................................................................39 2.10.3. SIRT6..........................................................................................40 2.10.4. SIRT7..........................................................................................40 3. Cellular senescence.......................................................................................................40 3.1. Causes of cellular senescence.......................................................................41