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DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces Cerevisiae

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DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces Cerevisiae YEASTBOOK GENOME ORGANIZATION & INTEGRITY DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae Serge Boiteux* and Sue Jinks-Robertson†,1 *Centre National de la Recherche Scientifique UPR4301 Centre de Biophysique Moléculaire, 45071 Orléans cedex 02, France, and yDepartment of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710 ABSTRACT DNA repair mechanisms are critical for maintaining the integrity of genomic DNA, and their loss is associated with cancer predisposition syndromes. Studies in Saccharomyces cerevisiae have played a central role in elucidating the highly conserved mech- anisms that promote eukaryotic genome stability. This review will focus on repair mechanisms that involve excision of a single strand from duplex DNA with the intact, complementary strand serving as a template to fill the resulting gap. These mechanisms are of two general types: those that remove damage from DNA and those that repair errors made during DNA synthesis. The major DNA-damage repair pathways are base excision repair and nucleotide excision repair, which, in the most simple terms, are distinguished by the extent of single-strand DNA removed together with the lesion. Mistakes made by DNA polymerases are corrected by the mismatch repair pathway, which also corrects mismatches generated when single strands of non-identical duplexes are exchanged during homologous recombination. In addition to the true repair pathways, the postreplication repair pathway allows lesions or structural aberrations that block replicative DNA polymerases to be tolerated. There are two bypass mechanisms: an error-free mechanism that involves a switch to an undamaged template for synthesis past the lesion and an error-prone mechanism that utilizes specialized translesion synthesis DNA polymerases to directly synthesize DNA across the lesion. A high level of functional redundancy exists among the pathways that deal with lesions, which minimizes the detrimental effects of endogenous and exogenous DNA damage. TABLE OF CONTENTS Abstract 1025 Introduction 1027 Direct Reversal of DNA Damage 1027 Phr1, pyrimidine dimer DNA photolyase 1028 Mgt1, O6-methylguanine/O4-methylthymine DNA methyltransferase 1028 Base Excision Repair 1028 DNA N-glycosylases 1029 Ung1, uracil-DNA N-glycosylase 1: 1029 Mag1, methylpurine-DNA N-glycosylase 1: 1029 Ntg1 and Ntg2, endonuclease III homologs: 1029 Ogg1, 8-oxoguanine-DNA N-glycosylase 1: 1030 GO network: 1030 Continued Copyright © 2013 by the Genetics Society of America doi: 10.1534/genetics.112.145219 Manuscript received September 19, 2012; accepted for publication December 5, 2012 1Corresponding author: Department of Molecular Genetics and Microbiology, 213 Research Dr., DUMC 3020, Duke University Medical Center, Durham, NC 27710. E-mail: sue. [email protected] Genetics, Vol. 193, 1025–1064 April 2013 1025 CONTENTS, continued AP endonucleases 1031 Apn1, AP endonuclease 1: 1031 Apn2, AP endonuclease 2: 1031 Origin, repair, and biological impact of endogenous AP sites: 1031 Single-strand break repair: “dirty end” processing factors 1032 Processing 39-dirty ends: 1032 Processing 59-dirty ends: 1032 DNA polymerase and DNA ligase 1032 Nucleotide Excision Repair 1033 Recognition of lesions during GG-NER 1033 Rad4-Rad23-Rad33 and Rad34: 1033 Rad7-Rad16-Abf1 and Rad7-Rad16-Cul3-Elc1: 1034 Formation of an open-structure and pre-incision complex 1035 TFIIH: 1035 Rad14: 1036 RPA: 1036 Dual incision 1036 Rad1-Rad10 complex: 1036 Rad2: 1036 Resynthesis and ligation 1036 TC-NER 1036 Rad26 and Rad28: 1037 Model for Rad26-dependent TC-NER: 1037 Rpb9 subpathway: 1037 TC-NER at AP sites: 1038 Additional Remarks Concerning NER Mechanisms 1038 Mismatch Repair 1038 Bacterial paradigm 1038 MutS homologs 1039 Recognition specificities of MutSa and MutSb: 1039 Central role of ATP binding/hydrolysis: 1039 Structural studies of MutS complexes: 1040 MutSg, the Msh4-Msh5 complex: 1040 MutL homologs 1041 MutLa, the Mlh1-Pms1 complex: 1041 Interaction of MutSa and MutSb with MutLa: 1041 MutLg, the Mlh1-Mlh3 complex: 1041 Other proteins important for MMR 1042 PCNA sliding clamp: 1042 Exo1 exonuclease: 1042 Are there additional participants in MMR?: 1042 Putting it all together: the mechanism(s) of mismatch removal 1042 Temporal and spatial control of MMR: 1043 Origins of nicks: 1043 Mismatch removal: 1043 Ribonucleotide Excision Repair 1044 Bypass of DNA Damage 1044 Components of error-free bypass 1044 Rad6-Rad18 complex: 1044 Rad5 protein: 1045 Ubc13-Mms2 complex: 1045 Error-free PRR and recombination 1046 Continued 1026 S. Boiteux and S. Jinks-Robertson CONTENTS, continued Components of error-free and error-prone TLS 1046 Assaying TLS: 1047 Pol z, the Rev3-Rev7(-Pol31-Pol32) complex: 1047 Rev1, a deoxycytidyl transferase: 1047 Pol h: 1048 Post-translational modification of PCNA 1048 When and where does PRR occur? 1050 Summary and Future Directions 1050 NA damage is induced by exposure to environmental repair pathway encodes components required for the bypass Dagents and is generated spontaneously during normal cel- of damages that block replicative DNA polymerases. It should lular metabolism (reviewed by Friedberg et al. 2006). Reactive be noted that components of the other major DNA-damage re- oxygen species (ROS) are an unavoidable by-product of aerobic pair pathway—base excision repair—were absent among the metabolism and cause both base damage and strand breaks. early rad mutants and that most were identified biochemically. Additional spontaneous cellular reactions include the hydrolytic The second iteration of the Cold Spring Harbor yeast books loss of bases, especially purines, from the phosphodiester back- was published in 1991, a time when the emphasis was on bone, as well as the deamination and alkylation of bases. In cloning (usually by functional complementation of the mutant humans, it has been estimated that up to 100,000 spontaneous phenotype) and sequencing RAD genes and on purifying the DNA lesions are generated daily per cell (Hoeijmakers 2009). encoded proteins and defining their biochemical properties Environmental DNA-damaging agents include the ultraviolet (Friedberg et al. 1991). The current review will focus on the (UV) component of sunlight, which generates cyclobutane py- progress made in the intervening 20 years, which has truly rimidine dimers and oxidative base damage; ionizing radiation, been astounding. The damage-reversal and excision-repair which produces clusters of ROS that create double-strand DNA pathways that remove DNA damage will be summarized, with breaks; and base-damaging chemicals such as aflatoxins, benzo an emphasis on the roles that individual players have within the (a)pyrene, methyl chloride, and nitrosamines, which alter or de- defined pathway. A major area of new focus will be the mis- stroy base-pairing capacity. Because DNA damage has the poten- match repair system, which is responsible for removing errors tial to inhibit and/or alter fidelity of replication and transcription, made during DNA replication. The only yeast mismatch repair there is a need for diverse and highly accurate repair processes. gene known in 1991 was PMS1, and rapid progress has been There is also a need for bypass mechanisms that allow unre- made in identifying other mismatch repair components and paired damage to be tolerated if encountered during replication. unraveling their molecular mechanisms. In addition, recent An emerging theme in the past 20 years is that there is consider- studies indicate that ribonucleoside monophosphates are fre- able overlap between the various repair and bypass pathways in quently incorporated into genomic DNA, and a pathway for terms of the cognate lesions that each can deal with. This func- their removal has been described. Finally, the postreplication tional redundancy is partially a reflection of the very high load of repair pathway, which is a tolerance/bypass pathway rather endogenous DNA damage and underscores the importance of than a true repair pathway, will be considered. The most sig- these pathways in the maintenance of genome stability. nificant advances with relation to this pathway have been the The first comprehensive review of yeast DNA-repair characterization of specialized translesion synthesis DNA poly- pathways was published as part of the 1981 Cold Spring merases and the discovery that post-translational modification Harbor yeast books (Haynes and Kunz 1981). Studies at that of proliferating cell nuclear antigen (PCNA) regulates alterna- time had focused on identifying the genes involved in sur- tive mechanisms of lesion bypass. The repair of double-strand viving treatment with UV light and ionizing radiation (RAD breaks, which occurs primarily via homologous recombination genes) and on using epistasis analysis to place the genes into in yeast, is covered in another review in this series and will not discrete pathways. These early genetic studies identified be considered here. Importantly, all of these pathways exhibit three discrete pathways, with each being named for the high evolutionary conservation, with discoveries made in the gene whose mutation conferred the most severe phenotype. budding yeast Saccharomyces cerevisiae serving as a paradigm The RAD3 epistasis group encodes components of the nucle- for repair processes in higher eukaryotes. otide excision repair pathway, which is the major pathway Direct Reversal of DNA Damage for repairing UV-induced lesions; the RAD52 epistasis group encodes components of the homologous
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