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CLONING and CHARACTERIZATION of EXCISION Repam GENES CLONING AND CHARACTERIZATION OF EXCISION REPAm GENES CLONING AND CHARACTERIZATION OF EXCISION REPAIR GENES KLONERING EN KARAKTERISERING VAN EXCISIE HERSTEL GENEN PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR AAN DE ERASMUS UNIVERSITElT ROTTERDAM OP GEZAG VAN DE RECTOR MAGNIFICUS PROF. DR. P.W.C. AKKERMANS M.A. EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN. DE OPEN BARE VERDEDIGING ZAL PLAATSVINDEN OP WOENSDAG 27 MAART 1996 OM 13:45 UUR DOOR PETRUS JOHANNES V AN DER SPEK GEBOREN TE DELFr PROMOTIECOMMISSIE Promotoren: Prof. Dr. D. Bootsma Prof. Dr. J.H.J. Hoeijmakers Overige leden: Prof. Dr. LA. Grootegoed Prof. Dr. D. Lindhout Prof. Dr. Ir. A.A. van Zeeland The studies described in this thesis were carried out in the Medical Genetics Centre South-West Netherlands at the department of Cell Biology and Genetics Erasmus University Rotterdam. This project was financially supported by the Medical Genetics Centre and the Dutch Cancer Society. The printing of this thesis was financially supported by: Ames B. V., Autron B. V., Bio­ Rad Laboratories B.V., Biozym B.V., Eurogentec N.V., Het Kasteel van Rhoon, Pharmacia B.V., Schleicher & Schuell Nederland B.V. and Thieme's Echte Thee. Front cover Three dimensional representation of the protein structure of ubiquitin. In blue (identical) and in orange (similar) residues shared by the NER enzyme RAD23 The similar spacefilling model indicates the homologous residues of the conserved core. Molecular modeling and image processing was performed at the National Institutes of Health's division of computer research and technology, Bethesda. USA. Illustrations Mirko Kuit Printing Drukkerij Haveka B.V., Alblasserdam The known is finite, the unknown infinite; intellectually we stand on an island in the midst of an illimitable ocean of inexplicability. Our business in every generation is to reclaim a little more land. Het bekende is eindig het onbekende oneindig; verstandelijk staan we op een eilandje midden in een onmetelijke oceaan van onverklaarbaarheid. Het is onze plicht in elke generatie een beetje meer land droog te leggen. T.H. Huxley (1887) CONTENTS PREFACE ABBREVIATIONS 6 CHAPTER!. General introduction 7 Overview and scope of this thesis II CHAPTER II. DNA repair mechanisms 13 Introductory comments 15 DNA lesions 16 DNA repair: Genes and mechanisms 21 Pathways and evolution 21 Nucleotide excision repair (NER) 23 Postreplication repair 30 Recombination repair 32 Repair syndromes and cancer 37 NER: XPC. HHR23 proteins and ubiquitin 42 References 49 CHAPTER III. Cloning of repair genes by sequence homology 63 Introduction to sequence comparison 65 Identification of RAD23, SNMI, PHR, XPE, and RAD9 equivalents 69 Detection of loosely defined functional domains 85 Significance and implications 89 References 91 CHAPTER IV. Purification and cloning of a nucleotide excision repair complex involving the xeroderma pigmentosulll group C protein and a human homologne of yeast RAD23. Masufani, c., Sugasmva,. K., Yanagismva, J., SOlloyamG, T., Vi, M., Enemota, T., Takio, K., Tanaka, K., Van del' Spek, P.J., Boolsma, D., Hoeijmakers, J.H.J. and Hanaoka, F. (EMBO J. 13: 1831-1843, 1994) 97 CHAPTER V. Chromosomal localization of three repair genes: the xerodeI1na pigmentoSlllll group C gene and two human homologs of yeast RAD23. Vall del' Spek, P.J., Smil, E.M.E., Bever/oo, H.B., Sugasawa, K., Maslllalli, C., Hallaoka, F., Hoeijmakers, J.H.J. alld Hagemeijer, A. (Genomics 23: 651-658, 1994) 129 CHAPTER VI. Cloning, comparative mapping and RNA expression of the mouse homologs of the S. cerevisiae nucleotide excision repair gene RAD23. Peter J. vall der Spek, Cecile Visser, Fumio Hanaoka, Rep Smit, Anne Hagemeijer. Dirk Rootsma and Jail H.J. Hoeijmakers. (Genomics 31: 20-27, 1996) 151 CHAPTER VII. Requirement of HHR23B, a human RAD23 homologue, for nucleotide excision repair ill vitro as a stimulatory factor of the XPC protein. Kaoru Sugasmva. Chikahide Masutani. Aldo Uchida. Takafumi Maekmva. Peter J. van del' Spek, Dirk Rootsma. Jail Fl.J. Hoeijmakers alld Fumio Hanaoka. (Submitted, 1995) 171 CHAPTER vm. XPC and hmnan homologs of RAD23: intracellnlar localization and relationship to other nucleotide excision repair complexes. Peter J. van del' Spek, Andre Eker, Suzanne Rademakers, Cecile Visser, Kaoru Sugasawa, Chikahide Masutani, FUII/io Hanaoka, Jan H.J. Hoeijll/akers and Dirk Rootsma. (Submitted, 1996) 197 CHAPTER IX. Concluding remarl<s 225 General considerations 227 Future directions 230 References 232 SUMMARY 235 SAMENVATTING 238 CURRICULUM VITAE 243 ACKNOWLEDGEMENTS 246 ABBREVIATIONS Ab antibody NER nucleotide excision repair AP apurinic or apyrimidinic (site in DNA) um nanometer AT ataxia telangiectasia NMR nuclear magnetic resonance DER base excision repair PAGE polyacrylamide gel electrophoresis BLAST basic local aliglllllcnt search tool PBS phosphate~buffered saline bp base pairs PCNA proliferating cell nuclear aotigen DS Bloom syndrome PCR polymerase chain reaction BSA bovine serum albumin PFGE pulsed field gel electrophoresis CDK CyClill dependent kinase PHR photoreactivation DNA photolyase eDNA complementary DNA RAD radiation sensitive CHO chinese hamster ovary REV defective mutation reversion CPD cyclobulanc pyrimidine dimer RPA replication protein A CS Cockayne syndrome RF-C replication factor C DAPI 4' 6-diamino-2-phenylindole RFLP restriction fragment length polymorphism DDD damaged DNA binding protein RNA ribonucleic acid DDD) DNA database Japan RPA replication protein A DNA deoxyribollucleic acid SAD S phase arrest deficient DNA-PK DNA dependent protein kinase scid severe combined immunodeficiency dNTP 2'-deoxynucleoside 5' -triphosphate SDS sodium dodecyJ sulphate DSBs double strand breaks SNM sensitive nitrogen mustard DTI dithiothreitol SSBs single strand breaks EDTA ethylene dinitrilo tetraacetic acid SSL suppressor stem loop EMBL European molecular biology laboratory STS sequence tagged site ERCC excision repair cross complementing SV40 Simian virus 40 EST expressed sequence tag TCR transcription coupled repair FA Fanconi anemia TFIIH transcription initiation factor llH (BTF2) FADHl 1,5-dihydroflavin adenine dinucleotide TRlS tris(hydroxymethyl)aminometliane FCS fetal calf serum TID lrichotliiodystrophy FISH fluorescence ill situ hybridization UBC ubiquitin conjugating FTP file transfer protocol UDS unscheduled DNA synthesis GDB Genome Data Base UV ultraviolet GGR global genome repair UVA ultraviolellight (315-400 nm) HHR23 hwnan homolog of RAD23 UVB ultraviolet light (280-315 nm) HLA histocompatibility antigens UVC ultraviolet light (280-320 nm) HNPCC hereditary Ilonpolyposis colorectal cancer uvr ultraviolet resistance Ig inmlUlloglobulin V(D») variable (diversity) joining ) Joule www world wide web kb kilobase XP xerodenna pigmentosum kD kilo Dalton XP-C XP complementation group C MEC mitotic entry control XRCC X-ray repair cross-complementing MTHF 5,10-methenyltetrahydrofolate YAC yeast artificial chromosome MW molecular weight 6-4PP pyrimidine (6-4) pyrimidone photoproduct 6 CHAPTER I General introduction GENERAL INTRODUCTION For all living organisms, it is of vital importance to maintain intact the genetic information stored in the nucleotide sequence of DNA. Numerous environmental and genotoxic agents can affect the DNA and lead to, for example, mutagenesis or carcinogenesis. Study of the mechanism of UV-carcinogenesis has become even more pressing given recent concerns about atmospheric ozone depletion (Mimms, 1994; Watson, 1995), because such atmospheric alterations would result in increased UVB at the earth's surface. Carcinogenesis appears to be a multistep process through which normal cells progress from benign, through transitional stages to the fully malignant forms of cancer by the gradual accumulation of genetic errors (Bishop, 1995). Therefore, normal cells have an intricate quality control mechanism that recognizes and mends damage to the DNA helix. A number of distinct DNA repair pathways have been identified. Such mechanisms counteract the process of carcinogenesis, and include nucleotide excision repair (NER), recombination repair, post-replication repair, mismatch repair. base excision repair and photoreactivation (reviewed in TIBS, DNA repair; Special issue vol 20, 1995). Impressive advances in our understanding of the biologic significance of these DNA repair pathways have come from studying human conditions in which the relevant genes are involved. The NER pathway is one of the most important pathways, since this recognizes and removes a wide range of DNA lesions. The fundamental importance of this mechanism is illustrated by three rare, autosomal, recessive, clinical conditions: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TID). Of the three disorders, XP has been studied in the greatest detail. The discovery that this cancer-prone syndrome is caused by defective NER was made in 1968 by Cleaver. NER-deficiency patients show a marked sensitivity to sun exposure. UV -exposed skin of XP patients shows pigmentation abnormalities and a greater than lOoo-fold increased risk of cancer, caused by defects in one of at least 7 different genes (XPA to XPG) (Cleaver and Kraemer, 1994). This clinical heterogeneity is also observed in CS, in which two complementation groups, CS-A and CS­ B, are distinguishable. The phenotype of CS patients includes sun sensitivity, but less severe than in XP, and stunted growth, neural dysmyelination and disturbed sexual development. Unlike XP, neither CS nor TID patients show an elevated risk
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