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Functions of SMUG1 and NEIL3 in Telomere Homeostasis

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Functions of SMUG1 and NEIL3 in Telomere Homeostasis Functions of SMUG1 and NEIL3 in telomere homeostasis Pinelopi Kroustallaki Thesis for the degree of Philosophiae Doctor (PhD) Department of Clinical Molecular Biology, Akershus University hospital Faculty of Medicine, University of Oslo Norway 2019 © Pinelopi Kroustallaki , 2020 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8377-629-4 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo. Educating the mind without educating the heart is no education at all. Aristotle 2 Acknowledgments The current PhD study was conducted at the Department of Clinical Molecular Biology (EpiGen) of Akershus University hospital and at the Research Institute of Internal Medicine of Oslo University Hospital, Rikshospitalet, from September 2015 to November 2019. Financial support was provided by University of Oslo and Akershus University hospital. First and foremost I would like to express my sincere gratitude to my principal supervisor, Professor Hilde Nilsen, for the opportunity she gave me to continue working in such an exciting project and be a part of a group that was making me to evolve as a scientist, day by day. Thank you for all the positivity, patience and guidance you showed me over these years. You could always find this perfect line between inspiration and motivation that could only push me to continue doing my job better. You will always be an example to follow in my professional life and I am grateful for that. I would like to thank my co-supervisor, Professor Magnar Bjøras, for all his time and help over the years. I would also like to thank all the co-authors and collaborators for their contribution and help in the current work. I am grateful that I had the opportunity to work among the current and past members of the Nilsen research group as well as all the colleagues at EpiGen. Lisa L, thank you for always being there for me, both as a colleague, ready to reply to all my questions, and as a very good friend. Henok K, Panpan Y, Ying E and Sergio C thank you for making the days at the lab feel sometimes like a playground. Tanima S, Anna W, Nuriye BT and Lene A, thank you for all the fruitful scientific discussions and for creating an environment at the office that many times felt like home. Also, a very big thank you to Anna Frengen for her immense patience, time and help, making sure everything work perfectly at EpiGen. I would like to express my gratitude to all the people in my life, outside academia that helped me through all the difficult moments of the past five years. To my friends, thank you for being by my side. Tassos, thank you for just being there for me, these years would not have been the same without you. Finally, there are no words to express how grateful I am to Γιώργος and Κατερίνα, my parents. You have always been supporting me throughout my life, making sure I will not fall. Thank you, the last five years would have never happened without you by my side. Oslo, December 2019 Penelope Kroustallaki 33 Table of Contents Abbreviations ...................................................................................................................... 5 List of papers....................................................................................................................... 7 Introduction ......................................................................................................................... 8 1. Telomeres-the end of chromosomes.......................................................................... 8 1.1 Structure of telomeric DNA ................................................................................................... 8 1.2 Telomeres and the DNA damage machinery .................................................................. 11 1.3 Telomeres and BER ............................................................................................................ 12 1.3.1 Molecular mechanism of BER ................................................................................. 13 1.3.2 BER glycosylases and Telomere homeostasis .................................................. 16 1.3.2.1 OGG1 ...................................................................................................................... 16 1.3.2.2 NEIL glycosylases ............................................................................................... 17 1.3.2.3 UNG ......................................................................................................................... 19 1.3.2.4 SMUG1 ................................................................................................................... 20 2. Telomeric elongation mechanisms............................................................................21 2.1 Telomerase structure and assembly ................................................................................. 22 2.1.1 hTERC and H/ACA RNP complex assembly ........................................................ 22 2.1.2 hTERT scaffolding and telomerase recruitment to telomeres ....................... 24 2.2 hTERC maturation ............................................................................................................... 26 3. Telomeres and ageing ................................................................................................30 4. Telomere homeostasis-Human vs Mouse.................................................................32 Aims of the study ...............................................................................................................34 Summary of papers............................................................................................................35 Discussion..........................................................................................................................38 References..........................................................................................................................52 Appendix.............................................................................................................................64 Paper I, II and III ..............................................................................................................64 44 Abbreviations 53BP1 p53-binding protein 1 5-caU 5-carboxyuracil AAG alkyladenine DNA-glycosylase AID activation-induced deaminase ALT alternative lengthening of telomeres AP site abasic site APE1 AP-endonuclease 1 ATM ataxia telangiectasia mutated ATR ataxia telangiectasia and Rad3 related BER base excision repair CB Cajal body CBCA cap-binding complex CM cardio myocytes CSR class switch recombination DCP2 decapping mRNA 2 factor DDR DNA damage response DGCR8 component DiGeorge critical region 8 DKC1 dyskerin pseudouridine synthase 1 DSBs DNA double strand breaks dsDNA double-stranded DNA FEN1 Flap endonuclease 1 G4 G-quadruplex structures Gh guanidinohydantoin hmU 5-hydroxymethyl uracil HR homologous recombination IFD insertion finger domain LigIII DNA ligase III LP long-patch repair MBD4 methyl-binding domain protein 4 MEFs mouse mbryonic fibroblasts MPG methylpurine DNA-glycosylase MRN Mre11/Rad50/ Nbs1 complex MUFA monounsaturated fatty acid MUTYH MutY-homolog glycosylase NAF1 nuclear assembly factor 1 NAFLD non-alcoholic fatty liver disease NEIL Nei endonuclease VIII-like family NER nucleotide excision repair NHEJ non - homologous end joining NTH1 Nth Endonuclease III-like 1 OOG1 8-oxoguanine-DNA glycosylase PABPN1 nuclear poly(A)-binding protein PAPD5 PAP-associated domain-containing protein’5 PARN Poly(A)-specific ribonuclease PD population doublings PML promyelocytic leukaemia bodies PNK polynucleotide kinase Pol β DNA polymerase β POT1 protection of telomeres 1 Rap1 Ras-related protein 1 5 RFC replication factor-C RNAPII RNA polymerase II RNP ribonucleoprotein RPA human replication protein A RTEL1 regulator of telomere elongation helicase 1 SHM somatic hypermutation SMUG1 single-strand-selective monofunctional uracil-DNA glycosylase 1 SNP single nucleotide polymorphism Sp spiroiminodihydantoin SP short-patch repair ssDNA single-stranded DNA TCAB1 telomere Cajal body protein 1 TDG thymine-DNA-glycosylase TERC telomeric RNA template TERT telomerase reverse transcriptase Tg thymine glycol TIF telomere dysfunction-induced foci TIN2 TRF1-interacting nuclear protein 2 TOE1 target of EGR1 protein 1 TPP1 tripeptidyl peptidase 1 TRAMP Trf4/Air2/Mtr4p Polyadenylation complex TRBD telomerase RNA binding domain TRF1 telomeric repeat factor 1 TRF2 telomeric repeat factor 2 UNG uracil DNA-glycosylase VSMCs vascular smooth muscle cells, WRN Werner syndrome helicase XRCC1 X-ray repair cross-complementing protein 1 XRN1 5΄-3΄ Exoribonuclease 1 6 List of papers Paper I Kroustallaki P, Lirussi L, Carracedo S, You P, Esbensen Y, Götz A, Jobert L, Alsøe L, Sætrom P, Gagos S, Nilsen H. SMUG1 promotes telomere maintenance through telomerase RNA end processing. Cell Rep. 2019 Aug 13;28 (7):1690-1702. Paper II Carracedo S, Kroustallaki P, Alsøe L, Segers F, Wang C, Bartosova Z, Bohov P, Tekin N, Esbensen Y, Kong XY, Chen L, Wennerstrøm A, Ceolotto D, Berge RK, Bruheim P, Wong G, Halvorsen B, and Nilsen H. Liver steatosis associated with telomere maintenance defects in Smug1-deficient mice. (Manuscript) Paper III Quiles-Jiménez A, Gregersen I, Segers FM, Skarpengland T, Kroustallaki P, Yang K; Kong XY, Lauritzen KH, Olsen
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