DNA excision repair pathways

Current Opinion in Genetics and Development

Volumn 7, Issue 2, 1997, Pages 158-169

  Lindahl, Tomas ^a   Karran, Peter ^a   Wood, Richard D ^a  

^a IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

DNA; NUCLEOTIDE;

ARTICLE; BASE MISPAIRING; COCKAYNE SYNDROME; EXCISION REPAIR; GENETIC TRANSCRIPTION; HUMAN; PRIORITY JOURNAL;

EID: 0030989228     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(97)80124-4     Document Type: Article

References (68)

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3. 147 with Ala, Cys, or Ser yields a thymine-DNA glycosylase. These results are entirely consistent with the current model for substrate binding by UDG. Expression of these enzymes in E. coli is toxic and expression at a low level confers a mutator phenotype on the cells. These enzyme derivatives might become useful as reagents for base-specific cleavage of DNA.
4. Gallinari P, Jiricny J: A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase. Nature 1996, 282:735-733. Previously, a distinct human DNA glycosylase that removes thymine at TG base-pairs was found, and the cDNA cloned. Using the cure region of the cDNA as a probe, a highly homologous sequence was identified and expressed from E. coli and Drosophila melanogaster. This second uracil-DNA glycosylase of E. coli is not inhibited by the UGI protein and does not work on AU base-pairs. It probably provides backup repair of deaminated cytosine residues. Drosophila does not have an enzyme corresponding to the major UDG of bacteria and mammalian cells, therefore the new enzyme might be the first line of defence against uracil in insect DNA.
5. Labahn J, Schärer OD, Long A, Ezaz-Nikpay K, Verdine GL, Ellenberger TE; Structural basis for the excision repair of alkylation-damaged DNA. Cell 1996, 86:321-329.
6. Yamagata Y, Kato M, Odawara K, Tokuno Y, Nakashima Y, Matsushima N, Yasumura K, Tomita K, Ihara K, Fujii Y et al.: Three-dimensional structure of a DNA repair enzyme, 3-methyladenine DNA glycosylase II, from Escherichia coli. Cell 1996, 86:311-319. In these two parallel independent studies [5,6*] the three-dimensional structure of the E. coli AlkA protein has bean established. The data show that substrate binding involves a flexible cleft between two helical domains in the enzyme, which allows the removal of several distinct damaged DNA bases in addition to the main substrate, 3-methyladenine. This versatility occurs at the expense of rapidity, in that this broad spectrum DNA glycosylase has a much lower turnover number than uracil-DNA glycosylase.
7. Thayer MM, Ahern H, Xing DX, Cunningham RP, Tainer JA: Novel DNA-binding motifs in trie DNA repair enzyme endonuclease III crystal structure. EMBO J 1995, 14:4108-4120. The 3D structure of E. coli endonuclease III is available at 1.85 Å resolution. Two novel DNA-binding motifs, a helix-hairpin-helix and a [4Fe-4S] cluster loop, surround a cleft with a solvent-filled pocket. Active-site residues are located at the mouth of the pocket.
8. Eide L, Bjørås M, Pirovano M, Alseth I, Berdal KG, Seeberg E: Base excision of oxidative purine and pyrimidine DNA damage in Saccharomyces cerevisiae by a DNA glycosylase with sequence similarity to endonuclease III from Escherichia coli. Proc Natl Acad Sci USA 1996, 93:10735-10740.
9. Roldan-Arjona T, Anselmino C, Lindahl T: Molecular cloning and functional analysis of a Schizosaccharomyces pombe homolog of Escherichia coli endonuclease III. Nucleic Acids Res 1996, 24:3307-3312.
10. Van der Kemp P, Thomas D, Barbey R, De Oliveira R, Boiteux S: Cloning and expression in Escherichia coli of the ogg1 gene of Saccharomyces cerevisiae, which codes for a DNA glycosylase that excises 7,8-dihydro-8-oxoguanine and 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine. Proc Natl Acad Sci USA 1996, 93:5197-5202.
11. Nash HM, Bruner SD, Scharer OD, Kawate T, Addona TA, Sponner E, Lane WS, Verdine GL: Cloning of a yeast 8-oxoguanine DNA glycosylase reveals the existence of a base excision DNA repair protein superfamily. Curr Biol 1996, 6:968-980.
12. Engelward BP, Dreslin A, Christensen J, Huszar D, Kurahara C, Samson L: Repair-deficient 3-methyladenine DNA glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation-induced chromosome damage and cell killing. EMBO J 1996, 15:945-952. Knockout mouse ES cells deficient in 3-methyladenine-DNA glycosylase were generated by targeted homologous recombination. The cells grow normally but are anomalously susceptible to chromosome damage and cytotoxicity by alkylating agents. Follow-up data on mice defective in this DNA glycosylase should be informative.
13. Kubota Y, Nash R, Klungland A, Schär P, Barnes D, Lindahl T: Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase β and the XRCC1 protein. EMBO J 1996, 15:6662-6670. Efficient repair of uracil-containing DNA occurs in the presence of purified human recombinant uracil-DNA glycosylase, AP endonuclease, DNA polymerase β, XRCC1 protein, and DNA ligase III. The XRCC1 protein apparently acts as a scaffold protein, facilitating the repair reaction by binding DNA ligase III at its carboxy and DNA polymerase β to its amino terminus.
14. Sobol RW, Horton JK, Kuhn R, Gu H, Singhal RK, Prasad R, Rajewsky K, Wilson SH: Requirement of mammalian DNA polymerase β in base excision repair. Nature 1996, 379:183-186. Attempts to construct knockout mice deficient in DNA polymerase β result in an early embryonic lethal phenotype. Enzyme-deficient embryonic fibroblasts can be recovered and propagated. These cells grow normally and are normally resistant to UV but show defective BER. The data provide evidence that polymerase β functions in BER but not in NER or DNA replication.
15. Matsumoto Y, Kim K: Excision of deoxyribose phosphate residues by DNA polymerase β during DNA repair. Science 1995, 269:699-702. The small amino-terminal domain of DNA polymerase β, distinct from the polymerization domain, is shown to be required for the catalytic excision of 5-deoxyribose-phosphate residues at incised abas c sites in DNA. Thus, DNA polymerase β has two distinct and obligatory functions during BER.
16. Frosina G, Fortini P, Rossi O, Carrozzino F, Raspaglio G, Cox LS, Lane DP, Abbondandolo A, Dogliotti E: Two pathways for base excision repair in mammalian cells. J Biol Chem 1996, 271:9573-9578.
17. Li X, Li J, Harrington J, Lieber MR, Burgers PMJ: Lagging strand DNA synthesis at the eukaryotic replication fork involves binding and stimulation of FEN-1 by proliferating cell nuclear antigen. J Biol Chem 1895, 270:22109-22112. FEN1, the 5′- 3′ exonuclease function of mammalian DNA replication is shown to interact with PCNA which, under some conditions, stimulated its nuclease activity.
18. Wood RD: DNA repair in eukaryotes. Annu Rev Biochem 1996, 65:135-167
19. 9. Sancar A: DNA excision-repair. Annu Rev Biochem 1996, 65:43-91.
20. Svejstrup J, Vichi P, Egly J-M: The multiple roles of transcription/repair factor TFIIH. Trends Biochem Sci 1996, 21:346-350
21. Sijbers AM, De Laat WL, Ariza RR, Biggerstaff M, Wei Y-F, Moggs JG, Carter KC, Shell BK, Evans E, De Jong MC et al.: Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease. Cell 1996, 86:311-822. A human gene homologous to budding yeast Rad1, fission yeast rad16, and Drosophila mei9 was isolated and found to correct the repair defect in XP-F group cells as well as rodent group 4 and group 11 NER mutants, indicating that all three groups are allelic. Causative mutations and much-reduced levels of protein were found in XP-F patients. XPF-ERCC1 was shown to be a structure-specific DNA endonuclease responsible for the 5́ incision during NER.
22. Brookman KW, Lamerdin JE, Thelen MP, Hwang M, Reardon JT, Sancar A, Zhou ZQ, Walter CA, Parris CN, Thompson LH: ERCC4 (XPF) encodes a human nucleotide excision repair protein with eukaryotic recombination homologs. Mol Cell Biol 1996, 16:5553-6562. The ERCC4 gene structure was determined and the corresponding cDNA isolated-and shown to correct NER mutants from rodent complementation groups 4 and 11. ERCC4 protein levels are reduced in cells from an XP-F patient. The homologous genes Rad1, rad16+, and mei-9 are known to have functions in both NER and recombination.
23. Ceska T, Sayers J, Stier G, Suck D: A helical arch allowing single-stranded-DNA to thread through T5 5′ -exonuclease. Nature 1996, 382:90-93. A report of the 2.5 Å crystal structure of the phage T5 5′-exonuclease, revealing an arch for binding DNA. A model is proposed for a threading mechanism in which single-stranded DNA could slide through the arch, which is formed by two helices, one containing positively charged and the other hydrophobic residues. The active site at the base of the arch contains two metal-binding sites.
24. 2+ in the proposed active site.
25. 4 footprinting experiments on a DNA molecule bearing a uniquely placed adduct. An unwound open complex spanning -25 nucleotides was observed that extended to the positions of 5′ and 3′ incision sites and was dependent on XPA protein and on ATR Opening during repair occurred prior to strand incision by XPG.
26. O'Donovan A, Davies AA, Moggs JG, West SC, Wood RD: XPG endonuclease makes the 3' incision in human DNA nucleotide excision repair, Nature 1994, 371:432-435.
27. Mu D, Hsu DS, Sancar A: Reaction mechanism of human DNA repair excision nuclease. J Biol Chem 1995, 271:8285-8294. Incision activity of human NER was reconstituted in a defined system. Six fractions that constituted the excision nuclease were required for dual incision of a thymine dimer. With a cholesterol-substituted oligonucleotide, excision occurred in the absence of XPC-HHR23B, reminiscent of transcription-coupled repair in XP-C mutant cell lines. With these lesjons, the normal levels of 3′-incision were produced in the absence of ERCC1-XPF. Kinetic experiments suggested that the 3′-incision precedes the 5′-incision, and uncoupled 5′-incision was never observed in the reconstituted system. Two forms of TFIIH were used in the reactions, one containing CDK7-cyclin H and one lacking it. Both forms were equally active in excision.
28. Moggs JG, Yarema KJ, Essigmann JM, Wood RD: Analysis of incision sites produced by human cell extracts and purified proteins during nucleotide excision repair of a 1.3-intrastrand d(GpTpG)-cisplatin adduct. J Biol Chem 1996, 271:7177-7186. Incisions around a 1,3 cisplatin intrastrand crosslink in DNA were mapped. The predominant sites were at the 9th phosphodiester band 3′ and the 16th bond 5′ to the lesion, yielding a 26Mer as the modal excision product. Oligonucleotides were formed at a rate indistinguishable from 3′ incision, suggesting that incisions are made nearly synchronously. Some uncoupled 5′ incisions were detected. In a purified system, all essential NER components were required in order to see either cleavage.
29. Reardon JT, Mu D, Sancar A; Overproduction, purification, and characterization of the XPC subunit of the human DNA-repair excision nuclease. J Biol Chem 1996, 271:19451-19456. Recombinant XPC and the XPC-HHR23B complex bound DNA, with slightly better binding to UV-damaged DNA. The XPC subunit alone was sufficient for reconstitution of dual incision in vitro and HHR23B did not stimulate the reaction.
30. Sugasawa K, Masutani C, Uchida A, Maekawa T, Van der Spek PJ, Bootsma D, Hoeijmakers JHJ, Hanaoka F: HHR23B, a human Rad23 homolog, stimulates XPC protein in nucleotide excision repair In vitro. Mol Cell Biol 1996, 16:4852-4361. Recombinant human XPC protein exhibited high affinity for single-stranded DNA and corrected the repair defect in XP-C whole-cell extracts, which contain excess endogenous HHR23B protein. XP-C cell extracts were fractionated to construct a reconstituted system in which neither endogenous XPC nor HHR23B proteins were present. In this assay system, XPC alone weakly corrected the repair defect and significant enhancement of the correcting activity was observed upon co-addition of HHR23B protein. Stimulation of XPC by HHR23B was found with simian virus 40 mini chromosomes as well as with naked plasmid DNA and with both UV- as well as N-acetoxy-2-acetylaminafluorene-induced DNA lesions.
31. Nichols AF, Ong P, Linn S: Mutations specific to the xeroderma pigmentosum group-E DDB(-) phenotype. J Biol Chem 1996, 271:24317-24320. Single-base alterations in the gene for the 48 kDa subunit were found in cells from three DDB(-) individuals but not in XP-E strains that have the activity. No mutations were found in the cDNA of the 127kDa subunit of DDB. Overexpression of p48 in Insect cells greatly increases DDB activity in the cells, especially if p127 is jointly overexpressed. The results indicate that p48 is required for DNA binding activity but, at the same time, necessitate further definition of the genetic basis of XP group E.
32. Ariza RR, Keyse SM. Moggs JG, Wood RD: Reversible protein phosphorylation modulates nucleotide excision repair of damaged DNA by human cell extracts. Nucleic Acids Res 1996, 24:433-440. The incision step of NER of damaged DNA by HeLa cell extracts is blocked strongly by the protein phosphatase inhibitors okadaic acid, microcystin-LR, and tautomycin. Full activity is restored by addition of Ser/Thr protein phosphatase 2A.
33. Gaillard PHL, Martini EMD, Kaufman PD, Stillman B, Moustacchi E, Almouzni G: Chromatin assembly coupled to DNA repair -a new role for chromatin assembly factor I. Cell 1996, 86:887-896. In Xenopus and human cell extract systems capable of carrying out NER and chromatin assembly, UV-dependent synthesis occurs simultaneously with chromatin assembly, indicating a mechanistic coupling between the two processes. Biochemical complementation in the human system shows that CAFI is necessary for the repair-associated chromatin formation.
34. Park MS, Knauf JA, Pendergrass SH, Coulon CH, Strniste GF, Marrone BL, MacInnes MA: Ultraviolet-induced movement of the human DNA repair protein, xeroderma pigmentosum type-G, in the nucleus. Proc Natl Acad Sci USA 1996, 93:8368-8373. Immunofluorescence localized XPG protein to foci in the nucleus and cell fractionation suggested that XPG protein forms a tight association with nuclear structures. In human skin fibroblast cells, the number of XPG foci decreases within two hours after UV irradiation, whereas total nuclear XPG fluorescence intensity remains constant, suggesting redistribution of XPG from foci to the nucleus overall. β-galactosidase-XPG fusion constructs transfected into HeLa cells indicates that the carboxy-terminal region of XPG is responsible both for foci formation and for the movement after UV irradiation.
35. Lehmann AR: Nucleotide excision-repair and the link with transcription. Trends Biochem Sci 1995, 20:402-405.
36. Friedberg EC: Relationships between DNA-repair and transcription. Annu Rev Biochem 1996, 65:15-42.
37. Hwang JR, Moncollin V, Vermeulen W, Seroz T, Van Vuuren H, Hoeijmakers JHJ, Egly JM: A 3′-5′ XPB helicase defect in repair/transcription factor TFIIH of xeroderma pigmentosum group-B affects both DNA repair and transcription. J Biol Chem 1996, 271:15898-15904. A frameshift mutation in the 3′ end of the XPB gene is responsible for the occurrence of both XP and CS in patient XP11 BE. TFIIH was isolated from cells derived from this individual and from the mother. The mutant TFIIH showed a reduced 3′→5′ XPB helicase activity, a severe NER defect, and a decrease in basal transcription activity in vitro. The latter defect may provide an explanation for rnany of the XP and CS symptoms that are difficult to rationalize based solely on an NER deficiency.
38. Iyer N, Reagan MS, Wu KJ, Canagarajah B, Friedberg EC: Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein. Biochemistry 1996, 35:2157-2167.
39. Habraken Y, Sung P, Prakash S, Prakash L: Transcription factor TFIIH and DNA endonuclease Rad2 constitute yeast nucleotide excision-repair factor-3′ - implications for nucleotide excision-repair and Cockayne syndrome. Proc Natl Acad Sci USA 1996, 93:10718-10722. TFIIH purified from a yeast strain that overexpresses Rad2 contained a stoichiometric amount of Rad2. Association with TFIIH might provide a means of targeting Rad2 10 the damage site, where its endonuclease activity would mediate the 3′ incision during NER.
40. Van Oosterwijk MF, Versteeg A, Filon R, Van Zeeland AA, Mullenders LHF: The sensitivity of Cockayne's syndrome cells to DNA-damaging agents is not due to defective transcription-coupled repair of active genes. Mol Cell Biol 1996, 16:4436-4444. The rate of excision of DNA adducts was measured in the adenosine deaminase gene of primary normal human fibroblasts and two CS (group A and B) fibroblast strains. In normal and CS cells, transcription-coupled repair does not contribute significantly to repair of dG-C8-AF in active genes. Yet CS cells are three-fold more sensitive to AAAF than are normal cells and are unable to recover the ability to synthesize RNA. The data rule out defective transcription-coupled repair as the cause of the increased sensitivity of CS cells to DNA-damaging agents and suggest that the cellular sensitivity and the prolonged repressed RNA synthesis are caused primarily by a transcription defect.
41. Bregman DB, Halaban R, Van Gool AJ, Henning KA, Friedberg EC, Warren SL: UV-induced ubiquitination of RNA polymerase II - a novel modification deficient in Cockayne syndrome cells. Proc Natl Acad Sci USA 1996, 93:11586-11590. A fraction of the large subunit of human RNA polymerass II is ubiquitinated shortly after exposure of cells to UV irradiation or cisplatin damage. This modification is deficient in fibroblasts representing Cockayne's syndrome groups A and B, and could be restored by introducing appropriate constructs containing the CSA or CSB genes.
42. Verhage RA, Van Gool AJ, De Groot N, Hoeijmakers JHJ, Van de Putte P, Brouwer J: Double mutants of Saccharomyces cerevisiae with alterations in global genome and transcription-coupled repair. Mol Cell Biol 1996, 16:496-502 Rad26 disruption mutants are defective in transcription-coupled repair but are not UV sensitive Double mutants of RAD26 with RAD7 or RAD16 were more UV sensitive than the single rad7 or rad16 mutants but not as sensitive as completely NER-deficient mutants. Analysis of dimer removal from the active RPB2 gene in the rad7/16 rad26 double mutants revealed some residual repair specific for the transcribed strand. Transcription has a role in this residual transcription-coupled repair that operates independently from Rad26.
43. L promoter. UvrAB was observed mainly to translocate in the 5′ to 3′ direction along the nontranscribed strand, as shown by induced supercoiling, and incise the opposite (transcribed) strand.
44. Selby CP, Sancar A: Structure and function of transcription-repair coupling factor. 2. Catalytic properties. J Biol Chem 1995, 270:4890-4395.
45. Mellon I, Champe GN: Products of DNA mismatch repair genes mutS and mutL are required for transcription-coupled nucleotide-excision repair of the lactose operon in Escherichia coli. Proc Natl Acad Sci USA 1996, 93:1292-1297. Removal of pyrimidine dimers from the individual strands of the induced lac operon is examined in UV-irradiated E. coli. Mutations in either of the DNA-mismatch correction genes mutS or mutL selectively abolish rapid repair in the transcribed strand and render the cells moderately sensitive to UV irradiation. Similar results were found in a strain with a mutation in the mfd gene, the product of which has been shown previously to be required for transcription-coupled repair in vitro.
46. Mellon I, Rajpal DK, Koi M, Boland CR, Champe GN: Transcription-coupled repair deficiency and mutations in human mismatch repair genes. Science 1996, 272:557-560 Several mismatch-repair-deficient tumor cell lines and HNPCC-derived lymphoblastoid cell lines are found to be deficient in transcription-coupled repair of UV-induced pyrimidine diners. The defect is corrected in a mutant cell line the mismatch repair deficiency of which had been corrected by chromosome transfer.
47. Sweder KS, Verhage RA, Crowley DJ, Grouse GF, Brouwer J, Hanawalt PC: Mismatch repair mutants in yeast are not defective in transcription-coupled DNA repair of UV-induced DNA damage. Genetics 1996, 143:1127-1135 Removal of UV-induced DNA damage is examined in S. cerevisiae strains mutated in mismatch repair genes. No defects are found in transcription coupled repair in yeast with mutations in the mismatch repair genes MSH2, MLH1, PMS1, and MSH3.
48. Modrich P, Lahue R: Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem 1996, 65:101-133.
49. Fishel R, Ewel A, Lee S, Lescoe MK, Griffith J: Binding of mismatched microsatellite DNA sequences by the human MSH2 protein. Science 1984, 266:1403-1405.
50. Drummond JT, Li G-M, Longley MJ, Modrich P: Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Science 1995, 268:1809-1912. Purified fractions from HeLa cells are used to restore the mismatch repair activity of LoVo cell extracts. The complementing factor, designated hMutSα, is shown to be a dimer of hMSH2 and a second protein of 160kDa. The purified complex binds to single base mispairs and one or three base loops. This paper demonstrates for the first time that correction of all mismatches is defective in extracts of cells carrying mutations in either hMSH2 and hMLH1, whereas certain other defective cells retain the ability to repair loops of more than two bases.
51. Palombo F, Gallinari P, Iaccarino I, Lettieri T, Hughes M, D'Arrigo A, Truong O, Hsuan JJ, Jiricny J: GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 1995, 268:1912-1914, The 160kDa mismatch recognition component is identified as GTBP, a second homologue of MutS previously identified as copurifying with hMSH2 mismatch binding activity using a GT mispaired substrate. Both hMSH2 and GTBP are shown to be required for mismatch binding. The colorectal carcinoma cell line DLD-1 is shown to be defective in mismatch recognition but to retain hMSH2.
52. Papadopoulos N, Nicolaides NC, Liu B, Parsons RE, Palombo F, D'Arrigo A, Markowitz S, Willson JKV, Kinzler KW, Jiricny J, Vogelstein B: Mutations of GTBP in genetically unstable cells. Science 1995, 268:1915-1917. The GTBP gene is mapped to chromosome 2p16, suggesting that GTBP and hMSH2 arose via a duplication event. Mutations in GTBP in tumor cells and in a mismatch-repair-defective cell line isolated in the laboratory are shown to confer a new type of selective microsatellite instability in regions of repeated mononucleotides. This is consistent with the limited mismatch repair deficiency in two of the cell lines. References [50*-52*] together provide direct evidence for two partially overlapping pathways of hMSH2-dependent mismatch recognition and indicated that defects in each pathway could confer different cellular phenotypes.
53. Palombo F, Iaccarino I, Nakajima E, Ikejima M, Shimada T, Jiricny J: hMutSβ, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr Biol 1996, 6:1181-1134. The alternative partner of hMSH2 in mismatch recognition is identified as hMSH2, a third human Mut3 homologue and the first to be described. The hMSH2-hMSH3 heterodimer, designated hMutSβ, was shown to bind preferentially to substrates containing larger unpaired loops.
54. Risinger JI, Umar A, Boyd J, Berchuck A, Kunkel TA, Barrett JC: Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Nat Genet 1996 14:102-105. Description of an endometrial carcinoma and a cell line (HHUA) derived from an endometrial carcinoma with mutations in hMSH3. The cell line exhibits mi crosatellite instability at mononucleotide, dinucleotide, trinucleotide, and tetranucleotide repeats. The instability is partially suppressed by expression of hMSH3-containing chromosome 5. Surprisingly, HHUA cells are also found to carry mutations in hMSH6/GTBP.
55. Aquilina G, Hess P, Branch P, MacGeoch C, Casciano I, Karran P, Bignami M: A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype. Proc Natl Acad Sci USA 1994, 91:8908-8909.
56. Li GM, Modrich P: Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs. Proc Natl Acad Sci USA 1995, 92:1950-1954. Purified fractions from HeLa nuclear extracts are used to restore the mismatch repair activity extracts prepared from the H6 subline of HCT116 colorectal carcinoma cells. The complementing factor, designated hMutLα, was shown to be a heterodimer of two homologues of the E coli MutL protein: hMLH1 and hPMS2. The purified complex restored the ability to correct single base mispairs and loops of up to four bases, suggesting that this complex is essential for correcting all mismatches.
57. Liu B, Parsons R, Papadopoulos N, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomäki P, De la Chapelle A et al.: Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 1996, 2:169-174. Analyzed tumors from 74 HNPCC kindreds. 68 are shown to have microsatellite instability. The known mismatch repair genes are sequenced in 48 kindreds and 34 mutations are identified. The vast majority (31) of these mutations are found to be roughly equally divided between hMSH2 and hMLH1. No mutations are found in hMSH6/GTBP.
58. Cip1/Waf1 may modulate mismatch repair through its interaction with PCNA and the PCNA requirement for correction is, at least partially, independent of its role in DNA replication.
59. Tishkoff D, Filosi N, Gaida GM, Kolodner RD: A novel mutation avoidance mechanism dependent on 5. cerevisiae RAD27 is distinct from DNA mismatch repair. Cell 1997, 88:253-253. Mutations in the RAD27 gene cause a strong mutator phenotypes mostly resulting in mutations in which sequences ranging from 5-108 bp flanked by direct repeats of 3-12 bp are duplicated. Mutation spectra and epistasis analysis indicate that Rad27 does not play a major role in MSH2-dependent mismatch repair. The duplication mutations may arise during DNA replication because extended strand-displacement synthesis can take place when Rad27 is absent, leading to transient out-of-register pairing in repeat structures to form an intermediate that leads to duplication.
60. Cip1/Waf1 and FEN1, suggesting that the ligands induce conformational changes in the PCNA trimer to ensure exclusive occupation.
61. De Wind N, Dekker M, Berns A, Radman M, Te Riele H: Inactivation of the mouse MSH2 gene results in postreplicational mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to tumorigenesis. Cell 1995, 82:321-330. In this study, knockout mice tor MSH2 were constructed. Extracts of homozygous defective cells are defective in mismatch binding. The cells exhibit microsatetlite instability, mutator and hyper-rec phenotypes and tolerance to methylating agents. Homozygous animals develop normally, are fertile but prone to thymic lymphomas with no clear indication of predisposition to colorectal or other malignancy.
62. -l- mice suggests that although the two proteins work in the same process, they may not do so in concert.
63. Baker SM, Bronner CE, Zhang L, Plug AW, Robatzek M, Warren G, Elliott EA, Yu JA, Ashley T, Arnheim N: Male mice defective in trie DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell 1995, 82:309-319. See annotation [64*].
64. -l-mice have microsatellite instability in somatic and germ cells, Both male and female hamozygous knockout mice are infertile and this correlates with abnormal spermatogenesis in males and disrupted oogenesis in females. Although chromosome pairing in spermatocytes is apparently normal, chiasmata formation and/or maintenance was defective resulting in premature separation of paired chromosomes. These observations probably indicate unsuccessful attempts at recombination and suggest that MLH1 is directly involved in meiotic crossing over.
65. O'Regan NE, Branch P, MacPherson P, Karran P: hMSH2-independent DNA mismatch recognition by human proteins. J Biol Chem 1996, 271:1789-1796. Describes an activity able to recognize mismatches in the standard bandshift assay which exhibits a preference for AC and certain other mispairs but also recognized some looped intermediates. The activity was extensively purified from wild-type cells and shown to be a heterodimer. It was present in wild-type levels in LoVo and DLD-1 cells and, therefore, independent of hMSH2 and hMSH6
66. Lindahl T, Satoh MS, Dianov G: Enzymes acting at strand interruptions in DNA. Philos Trans R Soc Lond Biol 1995, 247:57-62
67. Klungland A, Lindahl T: Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1). EMBO J 1997, in press.
68. Cip1 compete fur binding to the same site on PCNA: a potential mechanism to coordinate DNA replication and repair. Oncogene 1997, in press.