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PubMed1978

Excision repair of ultraviolet damage in mammalian cells. Evidence for two steps in the excision of pyrimidine dimers.

The incidence of pyrimidine dimer formation and the kinetics of DNA repair in African green monkey kidney CV-1 cells after ultraviolet (UV) irradiation were studied by measuring survival, T4 endonuclease V-sensitive sites, the fraction of pyrimidine dimers in acid-insoluble DNA as determined by thin layer chromatography (TLC), and repair replication. CV-1 cells exhibit a survival curve with extrapolation number n = 7.8 and Do = 2.5 J/m2. Pyrimidine dimers were lost from acid-insoluble DNA more slowly than endonuclease-sensitive sites were lost from or new bases were incorporated into high molecular weight DNA during the course of repair. Growth of CV-1 cultures in [3H]thymidine or X-irradiation (2 or 10 krads) 24 h before UV irradiation had no effect on repair replication induced by 25 J/m2 of UV. These results suggest that pyrimidine dimer excision measurements by TLC are probably unaffected by radiation from high levels of incorporated radionuclides. The endonuclease-sensitive site and TLC measurements can be reconciled by the assumption that pyrimidine dimers are excised from high molecular weight DNA in acid-insoluble oligonucleotides that are slowly degraded to acid-soluble fragments.

Cell Line↗

PubMed1998

Evaluation of cervical dysplasia treatment by large loop excision of the transformation zone (LLETZ). Does completeness of excision determine outcome?

OBJECTIVES: To evaluate the therapeutic and diagnostic potential of large loop excision of the transformation zone (LLETZ) in the management of cervical dysplasia (CD) when colposcopy is satisfactory; to determine if there is a relationship between completeness of excision and outcome. STUDY DESIGN: Ninety loop diathermies performed in the management of CD were studied prospectively. RESULTS: Eighty (88.89%) were indicated due to a high grade CD, 7 (7.78%) due to a low grade CD and 3 LLETZ (3.35%) due to a cytology-biopsy discordance. The margins were free of disease on 69 occasions (76.67%); on 15 (16.67%) the margins were affected by the disease and on 6 (6.67%) they were not evaluable. Using the Kaplan-Meier approach to survival analysis, the cumulative probability of continuing free of disease at the end of our study (36 months) was 0.89. In the margins free of disease group, patients stayed free of disease for an average of 32.98 months, and the cumulative probability of continuing free of disease at 36 months was 0.97. In the affected-margins group, patients stayed free of disease for an average of 20.91 months and the cumulative probability of continuing free of disease at 36 months dropped to 0.70. In the unevaluable-margins group, patients stayed free of disease for an average of 19.50 months and the cumulative probability of continuing free of disease at 36 months dropped still further to 0.67. Applying the Mantel-Cox Log-Rank Test we obtained differences among these three groups that are statistically significant (P<0.005). CONCLUSIONS: LLETZ could be considered the treatment of choice for CD when colposcopy is satisfactory, as it is effective, simple, fast, inexpensive, unaggressive, and of low morbidity. It also permits adequate pathology reporting. When a pathology report states that the margins of the specimen are not free of disease or are not evaluable, special caution in follow-up may be warranted.

Adult↗

PubMed2002

Base excision repair and nucleotide excision repair contribute to the removal of N-methylpurines from active genes.

Many different cellular pathways have evolved to protect the genome from the deleterious effects of DNA damage that result from exposure to chemical and physical agents. Among these is a process called transcription-coupled repair (TCR) that catalyzes the removal of DNA lesions from the transcribed strand of expressed genes, often resulting in a preferential bias of damage clearance from this strand relative to its non-transcribed counterpart. Lesions subject to this type of repair include cyclobutane pyrimidine dimers that are normally repaired by nucleotide excision repair (NER) and thymine glycols (TGs) that are removed primarily by base excision repair (BER). While the mechanism underlying TCR is not completely clear, it is known that its facilitation requires proteins used by other repair pathways like NER. It is also believed that the signal for TCR is the stalled RNA polymerase that results when DNA damage prevents its translocation during transcription elongation. While there is a clear role for some NER proteins in TCR, the involvement of BER proteins is less clear. To explore this further, we studied the removal of 7-methylguanine (7MeG) and 3-methyladenine (3MeA) from the dihydrofolate reductase (dhfr) gene of murine cell lines that vary in their repair phenotypes. 7MeG and 3MeA constitute the two principal N-methylpurines formed in DNA following exposure to methylating agents. In mammalian cells, alkyladenine DNA alkyladenine glycosylase (Aag) is the major enzyme required for the repair of these lesions via BER, and their removal from the total genome is quite rapid. There is no observable TCR of these lesions in specific genes in DNA repair proficient cells; however, it is possible that the rapid repair of these adducts by BER masks any TCR. The repair of 3MeA and 7MeG was examined in cells lacking Aag, NER, or both Aag and NER to determine if rapid overall repair masks TCR. The results show that both 3MeA and 7MeG are removed without strand bias from the dhfr gene of BER deficient (Aag deficient) and NER deficient murine cell lines. Furthermore, repair of 3MeA in this region is highly dependent on Aag, but repair of 7MeG is equally efficient in the repair proficient, BER deficient, and NER deficient cell lines. Strikingly, in the absence of both BER and NER, neither 7MeG nor 3MeA is repaired. These results demonstrate that NER, but not TCR, contributes to the repair of 7MeG, and to a lesser extent 3MeA.

Adenine↗

PubMed2004

The potential roles of p53 tumor suppressor in nucleotide excision repair (NER) and base excision repair (BER).

The p53 tumor suppressor has long been envisaged to preserve genetic stability by the induction of cell cycle checkpoints and apoptosis. More recently, p53 has been implicated to play roles in DNA repair responses to genotoxic stresses. UV-damage and the damage caused by certain chemotherapeutics including cisplatin and nitrogen mustards are known to be repaired by the nucleotide excision repair (NER) pathway which is reportedly regulated by p53 and its downstream genes. There are evidences to suggest that the base excision repair (BER) induced by the base-damaging agent methyl methanesulfonate (MMS) is partially deficient in cells lacking functional p53. This result suggests that the activity of BER might be also dependent on the p53 status. In this review, we discuss the possibilities that p53 regulates BER as well as NER; these are one of the most significant potentials of p53 tumor suppressor for repairing the vast majority of DNA damages that is incurred from various environmental stresses.

Animals↗

PubMed1996

Transcription factor TFIIH and DNA endonuclease Rad2 constitute yeast nucleotide excision repair factor 3: implications for nucleotide excision repair and Cockayne syndrome.

Nucleotide excision repair (NER) of ultraviolet light-damaged DNA in eukaryotes requires a large number of highly conserved protein factors. Recent studies in yeast have suggested that NER involves the action of distinct protein subassemblies at the damage site rather than the placement there of a "preformed repairosome" containing all the essential NER factors. Neither of the two endonucleases, Rad1-Rad10 and Rad2, required for dual incision, shows any affinity for ultraviolet-damaged DNA. Rad1-Rad10 forms a ternary complex with the DNA damage recognition protein Rad14, providing a means for targeting this nuclease to the damage site. It has remained unclear how the Rad2 nuclease is targeted to the DNA damage site and why mutations in the human RAD2 counterpart, XPG, result in Cockayne syndrome. Here we examine whether Rad2 is part of a higher order subassembly. Interestingly, we find copurification of Rad2 protein with TFIIH, such that TFIIH purified from a strain that overexpresses Rad2 contains a stoichiometric amount of Rad2. By several independent criteria, we establish that Rad2 is tightly associated with TFIIH, exhibiting an apparent dissociation constant < 3.3 x 10(-9) M. These results identify a novel subassembly consisting of TFIIH and Rad2, which we have designated as nucleotide excision repair factor 3. Association with TFIIH provides a means of targeting Rad2 to the damage site, where its endonuclease activity would mediate the 3' incision. Our findings are important for understanding the manner of assembly of the NER machinery and they have implications for Cockayne syndrome.

Cockayne Syndrome↗

PubMed1984

Completion of excision repair patches in human cell preparations: identification of a probable mode of excision and resynthesis.

Excision repair of u.v. damage in human fibroblasts is more sensitive to inhibitors of DNA polymerase alpha (cytosine arabinoside, aphidicolin) than to an inhibitor of polymerase beta (dideoxythymidine), which indicates a greater role in repair for polymerase alpha than for polymerase beta. These inhibitors all generate shortened patches with free 3' termini; the detailed structure of these patches was investigated in permeable cells or isolated nuclei by degradation of DNA with exonuclease III and by resynthesis with DNA polymerase I (Klenow fragment) and T4 DNA ligase. The structure of the shortened patches appears to be a short stretch of DNA synthesized in the 5'----3' direction within a longer single-strand gap. The single-strand gap ahead of the 3' terminus can be bridged only by the combined action of polymerase and ligase. This structure implies that excision must involve removal of an oligonucleotide or widening of a gap by 5'----3' exonuclease action to produce a single-strand region wide enough to be a substrate for polymerase alpha. There is no evidence for structures generated by nick translation or strand displacement.

Aphidicolin↗

PubMed1997

Effects of nitrous acid treatment on the survival and mutagenesis of Escherichia coli cells lacking base excision repair (hypoxanthine-DNA glycosylase-ALK A protein) and/or nucleotide excision repair.

Deoxyinosine occurs in DNA by spontaneous deamination of adenine or by incorporation of dITP during replication. Hypoxanthine residues (HX) are mutagenic and give rise to A-T-->G-C transition. They are substrates for the Escherichia coli product of the alkA gene, the 3-methyl-adenine-DNA glycosylase II (ALK A protein). In mammalian cells and in yeast, HX is excised by the counterpart of ALK A protein, the ANPG or the MAG proteins respectively. We have investigated in vivo the contribution of the alkA gene to counteract the lethal and/or mutagenic effects of HX residues induced by nitrous acid treatment. Using an E.coli strain allowing the detection of A-T-->G-C transition, we show that the alkA mutant has a slightly increased spontaneous rate of mutation and about the same sensitivity when treated with HNO2 as compared with the wild-type strain. Using the E.coli alkA mutant carrying a multicopy plasmid expressing the ALK A protein or the ANPG protein, we barely observe any effect of HNO2 treatment on sensitivity and mutation rate of the bacteria. In contrast, the same experiment performed with a uvrA- strain, deficient in nucleotide excision repair (NER), shows that this mutant is extremely sensitive to HNO2 treatment. Furthermore, the sensitivity and the spontaneous mutation rate observed in the double mutant alkA- uvrA- are almost identical to those of the uvrA- mutant. Hence, NER has the major role in vivo for the repair of lethal and mutagenic lesions induced by HNO2.

Adenosine Triphosphatases↗

PubMed1979

The excision of N-methyl-N-nitrosourea-induced lesions from the DNA of Chinese hamster cells as measured by the loss of sites sensitive to an enzyme extract that excises 3-methylpurines but not O6-methylguanine.

An enzyme extract from Micrococcus luteus excises 3-methyladenine and 3-methylguanine but not O6-methylguanine, 7-methylguanine, 1-methyladenine or 7-methyladenine from DNA reacted with N-methyl-N-nitrosourea. The extract was used to detect lesions in the DNA of Chinese hamster cells treated in culture with N-methyl-N-nitrosourea. It was concluded that 3-methyladenine is excised from these cells with a half-life of about 2.3 h.

Animals↗

PubMed2000

Contribution of base excision repair, nucleotide excision repair, and DNA recombination to alkylation resistance of the fission yeast Schizosaccharomyces pombe.

DNA damage is unavoidable, and organisms across the evolutionary spectrum possess DNA repair pathways that are critical for cell viability and genomic stability. To understand the role of base excision repair (BER) in protecting eukaryotic cells against alkylating agents, we generated Schizosaccharomyces pombe strains mutant for the mag1 3-methyladenine DNA glycosylase gene. We report that S. pombe mag1 mutants have only a slightly increased sensitivity to methylation damage, suggesting that Mag1-initiated BER plays a surprisingly minor role in alkylation resistance in this organism. We go on to show that other DNA repair pathways play a larger role than BER in alkylation resistance. Mutations in genes involved in nucleotide excision repair (rad13) and recombinational repair (rhp51) are much more alkylation sensitive than mag1 mutants. In addition, S. pombe mutant for the flap endonuclease rad2 gene, whose precise function in DNA repair is unclear, were also more alkylation sensitive than mag1 mutants. Further, mag1 and rad13 interact synergistically for alkylation resistance, and mag1 and rhp51 display a surprisingly complex genetic interaction. A model for the role of BER in the generation of alkylation-induced DNA strand breaks in S. pombe is discussed.

Adenine↗

PubMed1999

Overlapping specificities of base excision repair, nucleotide excision repair, recombination, and translesion synthesis pathways for DNA base damage in Saccharomyces cerevisiae.

The removal of oxidative damage from Saccharomyces cerevisiae DNA is thought to be conducted primarily through the base excision repair pathway. The Escherichia coli endonuclease III homologs Ntg1p and Ntg2p are S. cerevisiae N-glycosylase-associated apurinic/apyrimidinic (AP) lyases that recognize a wide variety of damaged pyrimidines (H. J. You, R. L. Swanson, and P. W. Doetsch, Biochemistry 37:6033-6040, 1998). The biological relevance of the N-glycosylase-associated AP lyase activity in the repair of abasic sites is not well understood, and the majority of AP sites in vivo are thought to be processed by Apn1p, the major AP endonuclease in yeast. We have found that yeast cells simultaneously lacking Ntg1p, Ntg2p, and Apn1p are hyperrecombinogenic (hyper-rec) and exhibit a mutator phenotype but are not sensitive to the oxidizing agents H2O2 and menadione. The additional disruption of the RAD52 gene in the ntg1 ntg2 apn1 triple mutant confers a high degree of sensitivity to these agents. The hyper-rec and mutator phenotypes of the ntg1 ntg2 apn1 triple mutant are further enhanced by the elimination of the nucleotide excision repair pathway. In addition, removal of either the lesion bypass (Rev3p-dependent) or recombination (Rad52p-dependent) pathway specifically enhances the hyper-rec or mutator phenotype, respectively. These data suggest that multiple pathways with overlapping specificities are involved in the removal of, or tolerance to, spontaneous DNA damage in S. cerevisiae. In addition, the fact that these responses to induced and spontaneous damage depend upon the simultaneous loss of Ntg1p, Ntg2p, and Apn1p suggests a physiological role for the AP lyase activity of Ntg1p and Ntg2p in vivo.

DNA Damage↗

PubMed2002

Yeast RAD26, a homolog of the human CSB gene, functions independently of nucleotide excision repair and base excision repair in promoting transcription through damaged bases.

RAD26 in the yeast Saccharomyces cerevisiae is the counterpart of the human Cockayne syndrome group B (CSB) gene. Both RAD26 and CSB act in the preferential repair of UV lesions on the transcribed strand, and in this process, they function together with the components of nucleotide excision repair (NER). Here, we examine the role of RAD26 in the repair of DNA lesions induced upon treatment with the alkylating agent methyl methanesulfonate (MMS). MMS-induced DNA lesions include base damages such as 3-methyl adenine and 7-methyl guanine, and these lesions are removed in yeast by the alternate competing pathways of base excision repair (BER), which is initiated by the action of MAG1-encoded N-methyl purine DNA glycosylase, and NER. Interestingly, a synergistic increase in MMS sensitivity was observed in the rad26 Delta strain upon inactivation of NER or BER, indicating that RAD26 promotes the survival of MMS-treated cells by a mechanism that acts independently of either of these repair pathways. The galactose-inducible transcription of the GAL2, GAL7, and GAL10 genes is reduced in MMS-treated rad26 Delta cells and also in mag1 Delta rad14 Delta cells, whereas a very severe reduction in transcription occurs in MMS-treated mag1 Delta rad14 Delta rad26 Delta cells. From these observations, we infer that RAD26 plays a role in promoting transcription by RNA polymerase II through damaged bases. The implications of these observations are discussed in this paper.

Base Pairing↗

PubMed1995

Base excision repair of U:G mismatches at a mutational hotspot in the p53 gene is more efficient than base excision repair of T:G mismatches in extracts of human colon tumors.

Approximately 50% of mutations that inactivate the p53 tumor suppressor gene in the germline and in colon tumors are C to T transitions at methylation sites (CpG sites). These mutations are believed to be caused by an endogenous mechanism and spontaneous deamination of 5-methyl-cytosine to T is likely to contribute significantly to this high mutation rate. The resulting T:G mismatches created by this process have been hypothesized to be less efficiently repaired than U:G mismatches formed by deamination of C. We have, therefore, performed the first study to directly compare rates of T:G versus U:G base excision repair at identical sites observed to be mutated in the p53 gene using extracts of human normal colon mucosa and colon carcinoma tissue. Mismatched U was excised up to 6000-fold more efficiently than T, suggesting that differences in repair efficiencies are the major source of C to T transition mutations at CpG sites in human tissues. The data also suggests that T:G mismatches are repaired by additional mechanisms in human cells.

Base Sequence↗

PubMed1987

Comparative study of long-term effects of surgical excision and excision combined with radiotherapy or chemotherapy in breast cancer: an analysis of 192 cases.

Clinical data of 192 patients with breast cancer with a primary lesion of 2-5 cm (stage II according to the criteria recommended by the UICC) and with histopathologically confirmed positive axillary lymph nodes were analyzed. The patients were divided into three groups: 1) surgical excision alone; 2) surgery plus irradiation; and 3) surgery plus chemotherapy. It was shown that the 5-year survival rates for these groups were 40.5%, 61.0%, and 62.0%, respectively (P less than .05).

Adult↗

PubMed1991

Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man.

Attentional "set" shifting was assessed in a group of 20 neurosurgical patients with localized excisions of the frontal lobes, a group of 20 patients with unilateral temporal lobe lesions and a group of 11 patients who had undergone amygdalo-hippocampus removal. These three patient groups were compared with groups of both young (age-matched) and elderly normal control volunteers on a computerized test of visual discrimination learning involving both an intra- and an extra-dimensional shift. The frontal lobe group were selectively impaired in their ability to shift response set to a previously irrelevant dimension but not to shift attention to new exemplars of a previously relevant dimension. A similar pattern was observed in the elderly group of normal control volunteers. By comparison, both the temporal lobe patients and the amygdalo-hippocampectomy patients were unimpaired in their ability to perform either shift, although both groups had significantly prolonged selection latencies at the extra-dimensional shift stage of the task. These data are compared to previous findings from patients with idiopathic Parkinson's disease and are discussed in terms of a specific attentional set shifting deficit following frontal lobe damage.

Adult↗

PubMed1994

Expression of the excision repair gene, ERCC3 (excision repair cross-complementing), during mouse development.

Expression of the human ERCC3 (excision repair cross-complementing) gene in cells from patients with xeroderma pigmentosum (XP) group B (XP-B) corrects the defect in repair of UV light-induced DNA damage. XP-B is one of three groups of XP which exhibit the clinical symptoms of both XP and Cockayne's Syndrome (CS). CS and XP-B/CS patients develop severe neurological dysfunction during development. In order to explore the link between the defective gene and the neurological deficits in XP/CS, we have studied the expression of ERCC3 mRNA in developing mice by in situ hybridisation. ERCC3 was found to be ubiquitously expressed in cells from all regions and all developmental stages, from 9 day post-coitum embryo, to 15 day post-natal brain. In post-natal brain, regional differences in expression correlated with cell density and there was no evidence of cell specific or developmental alterations in levels of expression. These results indicate that the constitutively expressed gene does not perform a discrete developmental function. The neurological defects apparent in XP-B are likely to arise pleiotypically from the participation of ERCC3 in interactions with other elements involved in particular aspects of neurodevelopmental control. These results emphasise the developmental importance of genes whose primary functions are apparently unconnected with development.

Animals↗

PubMed2005

[Laparoscopic rectal excision for cancer using total mesorectaol excision (TME). Long term outcome of a series of 179 patients].

BACKGROUND: The purpose of this study was to evaluate the outcomes and the five-year survival of 179 consecutive patients with rectal carcinoma operated with a laparoscopic procedure between April 1992 and April 2003. METHODS: Patients with obstructing, bulky cancers were excluded from this study. Tumor stage was defined according to the TNM classification. Preoperative radiation therapy was offered to T(3) N(0) or N(+) patients (45 Gy). The laparoscopic-assisted technique included total mesorectal excision (TME), primary high vascular ligation, centrifugal dissection of the mesentery, and "no touch" technique. All the N+ patients received adjuvant chemotherapy. The outcomes were defined as five-years recurrence (local recurrence and distant metastasis) and the diseases-free survival. The survival rates were calculated with the Kaplan-Meier test. RESULTS: There were 108 males and 71 females, median age was 67 (range 39-88). There were 61 upper rectum localizations (34%), 68 middle rectum (38%) and 50 low rectum (28%). Twenty-nine patients required open conversion (16%). Surgical operative morbidity was 24% and medical morbidity was 4%. There were 60 stage I (40%), 25 stage II (16%), 49 stage III (32%), and 16 stage IV (10%). Ninety patients (71%) are alive and disease free, ten (5%) are alive with disease recurrence, and 37 patients (20%) are deceased. Only one case of trocar site implantation occurred after curative resection during an average follow up of 76 months. Five-year observed survival rate were 85% for stage I, 70% for stage II, and 63% for stage III. CONCLUSION: In our experience laparoscopic rectal resection could be done safely. The oncologic outcome was similar to that of open surgery. Further randomized trials will be necessary to confirm the value of this technique.

Adult↗

PubMed2001

Photoimmunology and nucleotide excision repair: impact of transcription coupled and global genome excision repair.

Ultraviolet (UV) light generates damage to DNA which is removed by a versatile mechanism called nucleotide excision repair (NER). There are two subpathways for NER: the transcription coupled repair (TCR) pathway which removes DNA damage from actively transcribed genes and the global genome repair pathway which removes damage throughout the genome. Most types of DNA lesions are processed more rapidly by TCR than by GGR. It is widely accepted that immunological processes play a pivotal role in the generation of skin tumours induced by exposure to ultraviolet light and first evidence is emerging that GGR and TCR play different roles in skin reactions such as erythema and delayed type hypersensitivity. The relationship between UV-induced responses of the skin and the two NER subpathways is discussed.

Animals↗

PubMed2006

Analysis of surgical treatments for circumferentially protruding haemorrhoids: complete excision with repair using flaps versus primary excision with secondary suture-ligation.

BACKGROUND: Circumferentially protruding haemorrhoids (CPH) are troublesome lesions for both patients and surgeons, and in most cases demand surgical intervention. However, such surgery carries the risks of complications and recurrence. This study compared two surgical procedures in order to identify the optimal approach for CPH. METHODS: All patients underwent an open haemorrhoidectomy for primary haemorrhoids, after which patients underwent either of the two procedures for secondary haemorrhoids. Group 1 (n = 104) comprised patients who underwent submucosal excision with repair using remnant anodermal flaps; this procedure was performed between 1991 and 1996. Group 2 (n = 113) comprised patients who underwent suture-ligation; this procedure was performed between 1997 and 2002. Surgical outcomes including surgical variables, wound healing, complications and patient satisfaction were compared between the two groups. RESULTS: For group 2, surgical time and duration of analgesic use (mean +/- SEM, 22 +/- 0 minutes and 3 +/- 0 days, respectively) were significantly shorter than for group 1 (28 +/- 1 minutes and 4 +/- 0 days, respectively; p < 0.001 for both comparisons). In terms of complication rates, there was no significant difference between group 2 (15 patients, 14%) and group 1 (25 patients, 22%), and most complications were satisfactorily treated using conservative management. Skin tags and perianal abscesses were more frequent in group 1 than in group 2. The final follow-up was undertaken at 6 months postoperatively, at which time there were no recurrences in patients of either group. For both groups, over 90% of patients reported that they were satisfied with the outcome of surgery. CONCLUSION: Although both surgical approaches were successful for treating CPH, open haemorrhoidectomy for primary haemorrhoids combined with suture-ligation for secondary haemorrhoids appears to be the optimal approach considering its rapidity, simplicity and lower associated costs.

Adult↗