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Regulation of Oxidative DNA Damage Repair by DNA Polymerase Λ and Mutyh by Cross-Talk of Posttranslational Modifications

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Regulation of Oxidative DNA Damage Repair by DNA Polymerase Λ and Mutyh by Cross-Talk of Posttranslational Modifications Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2011 Regulation of oxidative DNA damage repair by DNA polymerase lambda and MutYH by cross-talk of posttranslational modifications Markkanen, Enni Emilia Other titles: Regulation of oxidative DNA damage repair by DNA polymerase ฀ and MutYH by cross-talk of posttranslational modifications Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-57042 Dissertation Originally published at: Markkanen, Enni Emilia. Regulation of oxidative DNA damage repair by DNA polymerase lambda and MutYH by cross-talk of posttranslational modifications. 2011, University of Zurich, Faculty of Science. Regulation of Oxidative DNA Damage Repair by DNA Polymerase λ and MutYH by Cross-talk of Posttranslational Modifications Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Enni Emilia Markkanen von Stallikon, ZH Promotionskomitee Prof. Dr. Ulrich Hübscher (Vorsitz) Prof. Dr. Massimo Lopes Prof. Dr. Grigory Dianov (External expert) Zürich, 2012 TO MY FAMILY -­ ÄITI, ISI, TIIA, SHIVA, LITTLE FOOT AND PADDINGTON -­ FOR ALL THEIR LOVE AND ENDLESS SUPPORT. TABLE OF CONTENTS ABBREVIATIONS 4 SUMMARY 5 English 5 German 6 INTRODUCTION 7 General introduction 7 Oxygen as a friend and enemy: the 8-­oxo-­G problem 9 DNA POLYMERASES, THE KEY ENZYMES FOR DNA REPLICATION AND DNA REPAIR 10 DNA polymeraseh an enzyme with many functions 12 MutYH DNA glycosylase – the initiator of A:8-­oxo-­G repair 14 MutYH Associated Polyposis 14 MutYH germline mutations and Mismatch Repair 14 MutYH and age-­related diseases 15 MutYH -­/-­ cells and mice 15 Review: ‘Oxygen as friend and enemy: how to combat the mutational potential of 8-­oxo-­Guanine’ 17 5HFHQWGHYHORSPHQWVLQWKH¿HOGRIR[R*UHSDLU±DQXSGDWHVLQFH 31 Repair of 8-­oxo-­G lesions 31 DNA Polymeraseh MutYH DNA glycosylase 33 3RVWWUDQVODWLRQDOPRGL¿FDWLRQV 35 3KRVSKRU\ODWLRQDVSRVWWUDQVODWLRQDOPRGL¿FDWLRQ 35 Ubiquitination: the cell’s way to dispose of waste – and more 36 Ubiquitination and DNA repair 38 AIM OF THE THESIS: 40 Background Aim ORIGINAL MANUSCRIPTS 41 “Ubiquitylation of DNA Polymeraseh ” 41 “Regulation of oxidative DNA damage repair by DNA Polymeraseh and MutYH by cross-­talk of phosphorylation and ubiquitination” 47 “In vitro gap directed translesion DNA synthesis of an abasic site involving human DNA Polymerases¡ h and` ” 54 UNPUBLISHED RESULTS 66 7UDQVOHVLRQV\QWKHVLV¿GHOLW\DVVD\ 66 Introduction and background of the approach 66 Materials and methods 66 Production of the substrates for the assay 66 6HWXSRIWKHDOOHOHVSHFL¿F3&5 68 Assessment of the FauI restriction approach 68 Results 68 Transformation of gapped plasmids into mammalian cells 68 Repair of 8-­oxo-­G:A mismatch in vivo by MutYH Final remarks for alternative approaches 71 SUMMARY OF THE MAJOR FINDINGS 72 GENERAL DISCUSSION 73 CURRICULUM VITAE 81 ACKNOWLEDGEMENTS 84 INDEX OF FIGURES AND TABLES Table 1: An overview of DNA polymerase families and their members. 11 Figure 1: Schematic presentation of the subdomains of DNA polymeraseh . 12 Figure 2: Scheme of the protein phosphorylation and -­dephosphorylation reaction. 35 Figure 3: The 26S proteasome. 37 Figure 4: Schematic presentation of the gapped plasmids. 67 Table 2: Mutational analysis by restriction digestion versus sequencing 69 7DEOH &RPSDULVRQRIWKH$63&5WRUHVWULFWLRQDQDO\VLVDQGVHTXHQFLQJ 69 7DEOH 5HVXOWVIURP$63&5UHVWULFWLRQDQDO\VLVDQGVHTXHQFLQJIRU knockdown of Pols` eand d . Table 5: Results from transfection of gapped plasmids into different MEF cell OLQHVIRUKDQDO\VHGE\$63&5 ABBREVIATIONS In alphabetical order 8-­oxo-­G ....................GLK\GURR[RJXDQLQH A ................................Adenine base AFAP ........................Attenuated familial adenomatous polyposis AP site .......................$SXULQLFDS\ULPLGLQLFVLWHDEDVLFVLWH $3& ..........................Adenomatous polyposis coli protein APE1 ........................Apurinic/apyrimidinic endonuclease 1 A.thaliana .................Arabidopsis thaliana BER ..........................Base-­excision repair & ...............................&\WRVLQHEDVH &GN ...........................&\FOLQGHSHQGHQWNLQDVH &6 .............................&RFND\QHV\QGURP DNA ...........................Deoxyribonucleic acid DSB ..........................DNA double-­strand breaks E.coli ..........................Escherichia coli ES cells .....................Embryonic stem cells FAP ...........................Familial adenomatous polyposis FEN1 ........................Flap endonuclease 1 G ................................Guanine base H ...............................Histidine H2O2 ...........................+\GURJHQSHUR[LGHDQR[LGDWLYHDJHQW hmdUrd ......................K\GUR[\PHWK\OXUDFLODSURGXFWRIR[LGDWLYHDWWDFNRQWKHPHWK\O group of a T base +13&& .....................Hereditary non-­polyposis colon cancer K ...............................Lysine MAP ..........................MutYH associated polyposis MEF ..........................0RXVHHPEU\RQLF¿EUREODVW MMR ........................Mismatch repair MMS ..........................0HWK\OPHWKDQHVXOIRQDWHDQDON\ODWLQJDJHQW Mule ..........................E3 ubiquitin ligase Mule MutYH .......................MutYH DNA glycosylase NER ...........................Nucleotide-­excision repair NHEJ ........................Non-­homologous end-­joining Ogg1 ..........................Ogg1 DNA glycosylase 3&1$ ........................Proliferating cell nuclear antigen Pol ..............................DNA Polymerase PTM ..........................3RVWWUDQVODWLRQDOPRGL¿FDWLRQ R ...............................Arginine ROS ..........................Reactive oxygen species RP-­A .........................Replication Protein A S ................................Serine S.cerevisiae ................Saccharomyces cerevisiae SNP ............................Single-­nucleotide polymorphism SSB ...........................DNA single-­strand breaks SSL ...........................Synthethic sickness/lethality T ................................Thymine base T ................................Threonine 7&5 ..........................Transcription-­coupled repair TLS ............................Translesion synthesis Y ...............................Tyrosine 6 SUMMARY English WLVFUXFLDOIRUDFHOOWRPDLQWDLQWKHJHQHWLFLQIRUPDWLRQHQFRGHGLQ'1$DVVWDEOHDVSRVVLEOHLQRUGHUWRDYRLG deleterious diseases as cancer to establish themselves. Genomic stability relies heavily on components of various I'1$UHSDLUPDFKLQHULHVZKLFKFRQVWDQWO\JXDUGWKHJHQHWLFLQWHJULW\E\FRUUHFWLQJDPXOWLWXGHRIPLVWDNHVDQG GDPDJHVLQÀLFWHGRQWKHJHQRPH5HSDLU'1$3RO\PHUDVHV 3ROV VXFKDV3ROVȜDQGȕDUHVSHFLDOL]HGLQKDQGOLQJ GDPDJHG'1$H[SHUWO\EXWWKH\DOOH[KLELWFRQVLGHUDEO\UHGXFHG¿GHOLW\ZKHQUHSOLFDWLQJORQJVWUHWFKHVRIXQGDPDJHG '1$7KXVLWLVRISLYRWDOLPSRUWDQFHWKDWWKRVH3ROVDUHPHWLFXORXVO\UHJXODWHGDVWKHLUPLVUHJXODWLRQFRXOGLQGXFH the establishment of mutations. 8-­oxo-­G is an abundant and highly miscoding oxidative DNA lesion arising from a YDULHW\RIH[RJHQRXVDQGHQGRJHQRXVVRXUFHV,WKDVEHHQVKRZQWKDW$R[R*PLVPDWFKHVZKLFKDUHFDXVHGE\ LQFRUUHFWE\SDVVRIR[R*E\UHSOLFDWLYH3ROVFDQEHDFFXUDWHO\UHSDLUHGin vitro andin vivoby a repair pathway that is FRRUGLQDWHGE\0XW<+DQG3ROȜ3ROȜLVSKRVSKRU\ODWHGE\&GN&\FOLQ$LQWKHODWH6DQG*SKDVHVRIWKHFHOOF\FOH 7KLVSKRVSKRU\ODWLRQSURPRWHVVWDELOL]DWLRQRI3ROȜE\SUHYHQWLQJLWIURPEHLQJWDUJHWHGIRUSURWHDVRPDOGHJUDGDWLRQ E\XELTXLWLQDWLRQ+RZHYHUVRIDULWKDVUHPDLQHGDP\VWHU\KRZWKLVSKRVSKRU\ODWLRQDOORZVWKHVWDELOL]DWLRQRI3ROȜ PHFKDQLVWLFDOO\)XUWKHUPRUHLWLVXQFOHDUZKDWRWKHUIDFWRUV¿QHWXQHDQGLQÀXHQFHWKHFRQWURORIWKHOHYHOVRI3ROȜ DQGKRZWKHHQJDJHPHQWRI3ROȜLQDFWLYHUHSDLUFRPSOH[HVLVFRRUGLQDWHG,QWKHSUHVHQWHGWKHVLVLWLVVKRZQWKDWWKH (OLJDVH0XOHPHGLDWHVXELTXLWLQDWLRQRI3ROȜDQGWKXVWDUJHWVLWIRUGHJUDGDWLRQE\WKHXELTXLWLQSURWHDVRPHV\VWHP ,PSRUWDQWO\WKLVFRQWURORI3ROȜOHYHOVE\0XOHKDVIXQFWLRQDOFRQVHTXHQFHVIRUWKHDELOLW\RIPDPPDOLDQFHOOVWRGHDO ZLWKR[R*OHVLRQV)XUWKHUPRUHLWLVGHPRQVWUDWHGWKDWWKHSKRVSKRU\ODWLRQRI3ROȜE\&GN&\FOLQ$LQWHUIHUHV ZLWK0XOHPHGLDWHGGHJUDGDWLRQRI3ROȜ0HFKDQLVWLFDOO\SKRVSKRU\ODWLRQVWDELOL]HV3ROȜE\LQFUHDVLQJWKHDI¿QLW\ RI SKRVSKRU\ODWHG 3RO Ȝ WR LWV LQWHUDFWLRQ SDUWQHU WKH FKURPDWLQERXQG SURWHLQ 0XW<+ 7KLV HQKDQFHG LQWHUDFWLRQ SURPRWHVWKHUHFUXLWPHQWRI3ROȜWRWKHFKURPDWLQ6LQFH0XOHLVDSURWHLQIRXQGH[FOXVLYHO\LQWKHF\WRSODVPLWFDQ QRWXELTXLWLQDWHWKHFKURPDWLQERXQGIUDFWLRQRI3ROȜDQGWKXVQRWWDUJHWLWIRUSURWHDVRPDOGHJUDGDWLRQ&RQVHTXHQWO\ 0XW<+DSSHDUVWRSURPRWHWKHVWDELOLW\RISKRVSKRU\ODWHG3ROȜE\ELQGLQJLWWRFKURPDWLQLQWRDFWLYHR[R*UHSDLU FRPSOH[HVZKHUHLWFDQQRWEHPRGL¿HGE\0XOH2QWKHRWKHUKDQGWKHIUDFWLRQRI3ROȜWKDWLVQRWHQJDJHGLQDFWLYH UHSDLUFRPSOH[HVRQFKURPDWLQLVORFDOL]HGWRWKHF\WRSODVPZKHUHLWLVVXEMHFWIRUSURWHDVRPDOGHJUDGDWLRQE\0XOH PHGLDWHGXELTXLWLQDWLRQ,QVXPPDU\LWLVDQLQWULFDWHUHJXODWRU\PHFKDQLVPLQYROYLQJWKHFURVVWDONRIWZRGLIIHUHQW 370VXELTXLWLQDWLRQDQGSKRVSKRU\ODWLRQWKDWDOORZVWKH¿QHWXQLQJRIWKHFHOOXODU3ROȜOHYHOVin time and space and thus contributes to the maintenance of genetic stability. 7 German VLVWYRQlXVVHUVWHU:LFKWLJNHLWIUHLQH=HOOHGDVVGLHLQGHU'1$NRGLHUWHJHQHWLVFKH,QIRUPDWLRQP|JOLFKVW NRQVWDQWJHKDOWHQZLUGXPGLH(WDEOLHUXQJYHUKHHUHQGHU)ROJHQYRQ0XWDWLRQHQ]XYHUPHLGHQZHOFKH]XP E%HLVSLHO ]XU .UHEVHQWVWHKXQJ IKUHQ N|QQHQ 'LH JHQHWLVFKH 6WDELOLWlW ZLUG GXUFK YLHOH YHUVFKLHGHQH '1$ 5HSDUDWXUPHFKDQLVPHQJHZlKUOHLVWHWZHOFKHGXUFKLKUH.RUUHNWXUIXQNWLRQHQGDV*HQRPVWlQGLJJHJHQHLQH9LHO]DKO YRQVFKlGOLFKHQ(LQÀVVHQYHUWHLGLJHQ'1$5HSDUDWXU3RO\PHUDVHQ 3ROV ZLH3ROh und` die sich auf
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