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PubMed2004

Excision margins in high-risk malignant melanoma.

BACKGROUND: Controversy exists concerning the necessary margin of excision for cutaneous melanoma 2 mm or greater in thickness. METHODS: We conducted a randomized clinical trial comparing 1-cm and 3-cm margins. RESULTS: Of the 900 patients who were enrolled, 453 were randomly assigned to undergo surgery with a 1-cm margin of excision and 447 with a 3-cm margin of excision; the median follow-up was 60 months. A 1-cm margin of excision was associated with a significantly increased risk of locoregional recurrence. There were 168 locoregional recurrences (as first events) in the group with 1-cm margins of excision, as compared with 142 in the group with 3-cm margins (hazard ratio, 1.26; 95 percent confidence interval, 1.00 to 1.59; P=0.05). There were 128 deaths attributable to melanoma in the group with 1-cm margins, as compared with 105 in the group with 3-cm margins (hazard ratio, 1.24; 95 percent confidence interval, 0.96 to 1.61; P=0.1); overall survival was similar in the two groups (hazard ratio for death, 1.07; 95 percent confidence interval, 0.85 to 1.36; P=0.6). CONCLUSIONS: A 1-cm margin of excision for melanoma with a poor prognosis (as defined by a tumor thickness of at least 2 mm) is associated with a significantly greater risk of regional recurrence than is a 3-cm margin, but with a similar overall survival rate.

Adolescent↗

PubMed2006

Repair of DNA-polypeptide crosslinks by human excision nuclease.

DNA-protein crosslinks are relatively common DNA lesions that form during the physiological processing of DNA by replication and recombination proteins, by side reactions of base excision repair enzymes, and by cellular exposure to bifunctional DNA-damaging agents such as platinum compounds. The mechanism by which pathological DNA-protein crosslinks are repaired in humans is not known. In this study, we investigated the mechanism of recognition and repair of protein-DNA and oligopeptide-DNA crosslinks by the human excision nuclease. Under our assay conditions, the human nucleotide excision repair system did not remove a 16-kDa protein crosslinked to DNA at a detectable level. However, 4- and 12-aa-long oligopeptides crosslinked to the DNA backbone were recognized by some of the damage recognition factors of the human excision nuclease with moderate selectivity and were excised from DNA at relatively efficient rates. Our data suggest that, if coupled with proteolytic degradation of the crosslinked protein, the human excision nuclease may be the major enzyme system for eliminating protein-DNA crosslinks from the genome.

Amino Acid Sequence↗

PubMed1981

Excision of transposon Tn5 is dependent on the inverted repeats but not on the transposase function of Tn5.

The excision of Tn5 from sites of insertion in the Escherichia coli genome was studied by examining the reversion of lac::Tn5 insertion mutations to lac+. We find that: (i) the frequency of excision depends on the site of Tn5 insertion, (ii) excision occurs efficiently in recA- cells, (iii) excision does not require a Tn5-encoded transposition function, and (iv) efficient excision requires the inverted repeats of Tn5. We propose that excision of Tn5 is similar to the formation of spontaneous deletions and occurs by slippage during DNA synthesis.

Chromosomes, Bacterial↗

PubMed1984

Unusual alleles of recB and recC stimulate excision of inverted repeat transposons Tn10 and Tn5.

Precise and nearly precise excision of transposon Tn10 occur by host-mediated processes unrelated to transposition. Both types of excision involve interactions between short (9 or 24 base-pair) direct repeat sequences at or near the termini of the transposon and are stimulated by the large (1,329-base-pair) inverted repeats that form the ends of Tn10. We describe here three mutations of Escherichia coli K-12, designated texA, that enhance excision of Tn10 and of the structurally analogous transposon Tn5. Genetic mapping and complementation analysis show that these mutations are unusual alleles of the recB and recC genes that alter but do not abolish RecBC function. As Tn10 excision normally does not depend on RecA or RecBC functions, texA mutations appear to provide another pathway for excision that depends on altered RecBC function; for one texA allele, excision has become dependent on RecA function as well. The available evidence suggests that texA mutations alter the stimulatory interaction between the inverted repeats of Tn10.

Alleles↗

PubMed2001

DNA repair excision nuclease attacks undamaged DNA. A potential source of spontaneous mutations.

Nucleotide excision repair is a general repair system that eliminates many dissimilar lesions from DNA. In an effort to understand substrate determinants of this repair system, we tested DNAs with minor backbone modifications using the ultrasensitive excision assay. We found that a phosphorothioate and a methylphosphonate were excised with low efficiency. Surprisingly, we also found that fragments of 23-28 nucleotides and of 12-13 nucleotides characteristic of human and Escherichia coli excision repair, respectively, were removed from undamaged DNA at a significant rate. Considering the relative abundance of undamaged DNA in comparison to damaged DNA in the course of the life of an organism, we conclude that, in general, excision from and resynthesis of undamaged DNA may exceed the excision and resynthesis caused by DNA damage. As resynthesis is invariably associated with mutations, we propose that gratuitous repair may be an important source of spontaneous mutations.

Base Sequence↗

PubMed2005

The 3'-azido group is not the primary determinant of 3'-azido-3'-deoxythymidine (AZT) responsible for the excision phenotype of AZT-resistant HIV-1.

The mechanism of human immunodeficiency virus (HIV) 1 resistance to 3'-azido-3'-deoxythymidine (AZT) involves reverse transcriptase (RT)-catalyzed phosphorolytic excision of the chain-terminating AZT-5'-monophosphate (AZTMP). Primers terminated with AZTMP are generally better substrates for this reaction than those terminated with 2',3'-dideoxynucleoside-5'-monophosphate (2',3'-ddNMP) analogs that lack a 3'-azido moiety. This led to the hypothesis that the 3'-azido group is a major structural determinant for maintaining the primer terminus in the appropriate site for phosphorolytic excision of AZTMP by AZT-resistant (AZT(R)) RT. To test this hypothesis, we evaluated the incorporation, phosphorolytic excision, and antiviral activity of a panel of 3'-azido-2',3'-ddN including 3'-azido-2',3'-ddA (AZddA), 3'-azido-2',3'-ddC (AZddC), 3'-azido-2',3'-ddG (AZddG), AZT, and 3'-azido-2',3'-ddU (AZddU). The results indicate that mutations correlated with resistance to AZT (D67N/K70R/T215F/K219Q) confer resistance to the 3'-azidopyrimidine nucleosides (AZddC, AZT, and AZddU) but not to the 3'-azidopurine nucleosides (AZddA and AZddG). The data suggest that the presence of a 3'-azido group on the 3'-terminal nucleotide of the primer does not confer increased phosphorolytic excision by AZT(R) RT for all 3'-azido-ddNMP analogs. Thus, the 3'-azido group cannot be the only structural determinant important for the enhanced phosphorolytic excision of AZTMP associated with HIV resistance to AZT. Other structural components, such as the base, must play a role in defining the specificity of the excision phenotype arising from AZT resistance mutations.

Anti-HIV Agents↗

PubMed1997

An audit of 267 consecutively excised mammographically detected breast lesions 1989-1993.

Pathology reports and slides were reviewed from 267 mammographically detected impalpable breast lesions, excised after hookwire localisation. There were 182 benign and 85 malignant lesions (benign to malignant ratio of 2.1:1). The invasive cancers tended to be small (mean 13 mm; 50% < or = 10 mm), of low histologic grade (38% Grade I), with a low incidence of lymph node metastases (15%). A high proportion of pure duct carcinoma in situ (DCIS) lesions (21%) was found, and an unusually high proportion of invasive lobular carcinoma (17%). Preoperative fine needle aspiration (FNA) was performed in 95 (36%) cases, including 47 (18%) sampled using sterotactic guidance and 48 (18%) sampled by palpation. The absolute sensitivity of diagnosis of malignancy was 32% and 5% respectively. In 79% of carcinomas further operation was performed, for axillary clearance or re-excision of incompletely excised tumor; this high rate was largely a result of a decision not to use frozen section diagnosis for impalpable lesions and because of the early stages of the development of preoperative needle diagnosis. 58% of invasive cancers, including seven of eight (87.5%) carcinomas with an extensive intraduct component (EIC + ve), and 72% of DCIS were incompletely excised at the first operation. Residual tumor was found in the re-excisions in 26% of EIC - ve invasive carcinomas, 71% of the EIC + ve cases and 56% of DCIS lesions. The malignant lesions had highly favourable prognostic indices. The need for concentration of experience with pre-operative FNA was highlighted. Positive excision margins were a good predictor for residual malignancy, particularly for EIC + ve cases and for DCIS lesions.

Adult↗

PubMed1986

Effects of hyperthermia on radiation-induced chromosome breakage and loss in excision repair deficient Drosophila melanogaster.

Hyperthermia increased radiosensitivity with respect to gamma-ray induced chromosome loss and breakage in all stages of spermatogenesis in the wild type Oregon R strain of Drosophila melanogaster, whereas hyperthermia increased radiosensitivity to a lesser extent in cn mus (2) 201D1, an excision repair mutant with 0 per cent excision capacity and in mus (3) 308D1, a strain with 24 per cent excision capacity. The differences in hyperthermia-induced radiation sensitivity between the excision repair mutants and the wild strain may be due to the hyperthermia affecting the excision repair mechanism, suggesting that one of the possible mechanisms involved in hyperthermia-increased radiosensitivity is an effect on excision repair.

Animals↗

PubMed1989

Centrin-mediated microtubule severing during flagellar excision in Chlamydomonas reinhardtii.

Chlamydomonas cells excise their flagella in response to a variety of experimental conditions (e.g., extremes of temperature or pH, alcohol or detergent treatment, and mechanical shear). Here, we show that flagellar excision is an active process whereby microtubules are severed at select sites within the transition zone. The transition zone is located between the flagellar axoneme and the basal body; it is characterized by a pair of central cylinders that have an H shape when viewed in longitudinal section. Both central cylinders are connected to the A tubule of each microtubule doublet of the transition zone by fibers (approximately 5 nm diam). When viewed in cross section, these fibers are seen to form a distinctive stellate pattern characteristic of the transition zone (Manton, I. 1964. J. R. Microsc. Soc. 82:279-285; Ringo. D. L. 1967. J. Cell Biol. 33:543-571). We demonstrate that at the time of flagellar excision these fibers contract and displace the microtubule doublets of the axoneme inward. We believe that the resulting shear force and torsional load act to sever the axonemal microtubules immediately distal to the central cylinder. Structural alterations of the transition zone during flagellar excision occur both in living cells and detergent-extracted cell models, and are dependent on the presence of calcium (greater than or equal to 10(-6) M). Immunolocalization using monoclonal antibodies against the calcium-binding protein centrin demonstrate the presence of centrin in the fiber-based stellate structure of the transition zone of wild-type cells. Examination of the flagellar autotomy mutant, fa-1, which fails to excise its flagella (Lewin, R., and C. Burrascano. 1983. Experientia. 39:1397-1398), demonstrates that the fa-1 lacks the ability to completely contract the fibers of the stellate structure. We conclude that flagellar excision in Chlamydomonas involves microtubule severing that is mediated by the action of calcium-sensitive contractile fibers of the transition zone. These observations have led us to question whether microtubule severing may be a more general phenomenon than previously suspected and to suggest that microtubule severing may contribute to the dynamic behavior of cytoplasmic microtubules in other cells.

Animals↗

PubMed1991

Uncoupling of Chlamydomonas flagellar gene expression and outgrowth from flagellar excision by manipulation of Ca2+.

Chlamydomonas cells respond to certain environmental stimuli by shedding their flagella. Flagellar loss induces a rapid, transient increase in expression of a specific set of genes encoding flagellar proteins, and assembly of a new flagellar pair. While flagellar gene expression and initiation of flagellar outgrowth are normally tightly coupled to flagellar excision, our results demonstrate that these processes can be uncoupled by manipulating Ca2+ levels or calmodulin activity. In our experiments, wild-type cells were stimulated to excise their flagella using mechanical shearing, and at times after deflagellation, flagellar lengths were measured and flagellar mRNA abundance changes were determined by S1 nuclease protection analysis. When extracellular Ca2+ was lowered by addition of EGTA to cultures before excision, flagellar mRNA abundance changes and flagellar outgrowth were temporally uncoupled from flagellar excision. When extracellular Ca2+ was lowered immediately after excision or when calmodulin activity was inhibited with W-7, flagellar outgrowth was uncoupled from flagellar excision and flagellar mRNA abundance changes. Whenever events in the process of flagellar regeneration were temporally uncoupled, the magnitude of the flagellar mRNA abundance change was reduced. These results suggest that flagellar gene expression may be regulated by multiple signals generated from these events, and implicate Ca2+ as a factor in the mechanisms controlling flagellar regeneration.

Animals↗

PubMed2003

Source versus content memory in patients with a unilateral frontal cortex or a temporal lobe excision.

It has been suggested previously that patients with a frontal lobe lesion might have a specific impairment in the retrieval of the source of information despite adequate memory for facts. Patients with an anterior temporal excision are known to have impairments in memory for facts and the question arises as to whether they are also impaired in source memory. The present study compared memory for facts and their source in patients with a unilateral frontal cortical or an anterior temporal excision in a situation in which both types of information were encoded explicitly. Patients with a unilateral frontal cortex or a temporal lobe excision watched videos of a game show and were instructed to attend to both the trivia facts and their source (the identity of the speaker or the relative time of presentation). Patients with a frontal cortex excision were not impaired on either fact or source memory. This was true even when a subgroup of patients with an excision involving the dorsolateral frontal cortex was examined. In contrast, patients with a left temporal lobe excision were impaired in both fact and identity source memory and right temporal lobe patients were impaired in identity source memory. All patients performed similarly to normal controls in temporal source memory. The present results are consistent with the view that source information is part of an associative network of information about an episode and that the medial temporal region is critical for both source and content memory. Furthermore, if source information is encoded explicitly, the frontal cortex does not appear to be necessary for its retrieval. Instead, it is proposed that the frontal cortex plays a metacognitive role in memory retrieval.

Adolescent↗

PubMed1986

Quantitation of carcinogen-induced DNA damage and repair in human cells with the UVR ABC excision nuclease from Escherichia coli.

Recent studies by others have shown that the endonuclease complex coded for by the uvrA, uvrB and uvrC genes of Escherichia coli (UVR ABC excision nuclease) can incise DNA containing a variety of 'bulk-type' lesions, such as those resulting from u.v. light, (+/-)-7 alpha,8 beta-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE), and N-acetoxy-2-acetylaminofluorene. Using partially purified UVR ABC excision nuclease, we have quantitated the number of endonuclease sensitive sites (ESS) in purified DNA isolated from human fibroblasts treated with u.v. light or BPDE. The number of ESS/10(8) daltons of DNA were calculated from the number average mol. wt. of the DNA as determined by sedimentation in alkaline sucrose gradients. The number of endonuclease sites increased linearly with increasing doses of either u.v. light or BPDE. The UVR ABC excision nuclease was able to incise a majority of the BPDE-DNA adducts. Xeroderma pigmentosum fibroblasts, complementation group A (XP12BE) had 20-25% more ESS at each dose than the BPDE-treated normal (HSBP) cells. Cells treated with 4 microM BPDE and allowed 12 h of incubation to perform excision repair showed removal of 60% of the initial number of ESS from HSBP DNA and 40% of the ESS from XP-A DNA. Beyond 12 h XP12BE cells lost no additional ESS while HSBP cells continued to lose ESS, although at a slower rate, until at 48 h only 22% of the initial ESS remained. In cells treated with 10 J/m2 of u.v. light, the UVR ABC excision nuclease detected 60% of the sites recognized by the pyridimine dimer specific Micrococcus luteus glycosylase/apyrimidinic endonuclease. These results demonstrate the potential use of the UVR ABC excision nuclease in a quantitative assay for determining the number of carcinogen-induced lesions in human DNA.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1992

Molecular analysis of the maize wx-B3 allele indicates that precise excision of the transposable Ac element is rare.

The somatic and germinal behavior of the maize wx-B3 mutation indicates that this Ac allele rarely reverts. Endosperms containing wx-B3 display tiny and infrequent Wx revertant sectors while no significant reversion is detected when wx-B3 pollen is stained with I/KI. Previous studies of other transposable element alleles that revert infrequently have implicated low levels of element excision. Unlike these other alleles, the wx-B3 Ac element is indistinguishable from fully active Ac elements with respect to its structure, and its ability to transpose from the Wx gene or to trans-activate a Ds element. Characterization of somatic and germinal excision events lead us to conclude that excision of the wx-B3 Ac element almost always produces null alleles. Furthermore, the excellent correlation between the position of the wx-B3 mutation on the physical and genetic maps indicates that the Ac insertion is the only lesion of wx-B3. As a result, precise excision of this Ac should restore Wx function. The fact that revertant sectors and pollen grains are rare indicates that precise excision of Ac is also rare. The finding that the wx-B3 reversion frequency is comparable whether wx-B3 is hemizygous or over a wx allele with a wild-type insertion site illustrates a fundamental difference between the excision mechanisms of Ac and Drosophila P elements.

Alleles↗

PubMed1996

Adjacent sequences influence DNA repair accompanying transposon excision in maize.

Mobile elements transposing via DNA intermediates often leave small rearrangements, or "transposon footprints," at sites where they excise. Each excision event leaves its own footprint and, at any given site, these vary in size and sequence. Footprint formation involves DNA repair of sequences flanking the element. We have analyzed the footprints formed by a 2-kb Ds element excising from six different sites in exons of the maize waxy (Wx) gene. We find that groups of footprints left at individual sites are surprisingly nonrandom; different excision products predominate consistently at each site. Less frequent footprints left by each insertion appear related to the predominant type. The data suggest that flanking sequences affect the DNA repair processes associated with element excision. Two models have been proposed to explain footprint formation, one featuring a 5' exonuclease and the other featuring hairpin loop formation and an endonuclease. Our data have interesting implications for both these models. Evidence is also presented to support the presence of a separate excision mechanism that can remove Ac/Ds elements without leaving any footprint and that operates in parallel with the footprint-forming mechanism.

Alleles↗

PubMed1997

Kinetics of excision of purine lesions from DNA by Escherichia coli Fpg protein.

The kinetics of excision of damaged purine bases from oxidatively damaged DNA by Escherichia coli Fpg protein were investigated. DNA substrates, prepared by treatment with H2O2/Fe(III)-EDTA or by gamma-irradiation under N2O or air, were incubated with Fpg protein, followed by precipitation of DNA. Precipitated DNA and supernatant fractions were analyzed by gas chromatography/isotope-dilution mass spectrometry. Kinetic studies revealed efficient excision of 8-hydroxyguanine (8-OH-Gua), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) and 4, 6-diamino-5-formamidopyrimidine (FapyAde). Thirteen other modified bases in the oxidized DNA substrates, including 5-hydroxycytosine and 5-hydroxyuracil, were not excised. Excision was measured as a function of enzyme concentration, substrate concentration, time and temperature. The rate of release of modified purine bases from the three damaged DNA substrates varied significantly even though each DNA substrate contained similar levels of oxidative damage. Specificity constants (kcat/KM) for the excision reaction indicated similar preferences of Fpg protein for excision of 8-OH-Gua, FapyGua and FapyAde from each DNA substrate. These findings suggest that, in addition to 8-OH-Gua, FapyGua and FapyAde may be primary substrates for this enzyme in cells.

Animals↗

PubMed1979

Recovery of DNA synthesis after ultraviolet irradiation of xeroderma pigmentosum cells depends on excision repair and is blocked by caffeine.

Normal human and xeroderma pigmentosum (XP, excision-defective group A) cells (both SV40-transformed) pulse-labeled with [(3)H]thymidine at various times after irradiation with ultraviolet light showed a decline and recovery of both the molecular weights of newly synthesized DNA and the rates of synthesis per cell. At the same ultraviolet dose, both molecular weights and rates of synthesis were inhibited more in XP than in normal cells. This indicates that excision repair plays a role in minimizing the inhibition of chain growth, possibly by excision of dimers ahead of the growing point. The ability to synthesize normal-sized DNA recovered more rapidly than rates of synthesis in normal cells, but both parameters recovered in phase in XP cells. During recovery in normal cells there are therefore fewer actively replicating clusters of replicons because the single-strand breaks involved in the excision of dimers inhibit replicon initiation. XP cells have few excision repair events and therefore fewer breaks to interfere with initiation, but chain growth is blocked by unexcised dimers. In both cell types recovery of the ability to synthesize normal-sized DNA was prevented by growing cells in caffeine after irradiation, possibly because of competition between the DNA binding properties of caffeine and replication proteins. Our observations imply that excision repair and semiconservative replication interact strongly in irradiated cells to produce a complex spectrum of changes in DNA replication which may be confused with parts of alternative systems such as post-replication repair.

Caffeine↗

PubMed2003

High efficiency, site-specific excision of a marker gene by the phage P1 cre-loxP system in the yellow fever mosquito, Aedes aegypti.

The excision of specific DNA sequences from integrated transgenes in insects permits the dissection in situ of structural elements that may be important in controlling gene expression. Furthermore, manipulation of potential control elements in the context of a single integration site mitigates against insertion site influences of the surrounding genome. The cre-loxP site-specific recombination system has been used successfully to remove a marker gene from transgenic yellow fever mosquitoes, Aedes aegypti. A total of 33.3% of all fertile families resulting from excision protocols showed evidence of cre-loxP-mediated site-specific excision. Excision frequencies were as high as 99.4% within individual families. The cre recombinase was shown to precisely recognize loxP sites in the mosquito genome and catalyze excision. Similar experiments with the FLP/FRT site-specific recombination system failed to demonstrate excision of the marker gene from the mosquito chromosomes.

Aedes↗

PubMed1996

Complications of CO2-laser endoscopic excision of deep endometriosis.

The complications during and following endoscopic excision of deep endometriosis were analysed. The data of 225 excisions performed in 212 women had been collected prospectively into a database immediately following surgery and during the follow-up visit. The data confirmed the association of severe pelvic pain and deep endometriosis, severe pelvic being the only indication for surgery in 67, 78 and 76% of women with type I (n = 99), type II (n = 55) and type III (n = 71) lesions respectively. They confirmed that type II and type III were the largest lesions and that they were found predominantly in revised American Fertility Society (AFS) class II. The duration of surgery decreased with expertise (P < 0.01), but increased when deeper or larger lesions were excised (P < 0.0001) and when cystic ovarian endometriosis was also present (P < 0.001). Excision was clinically judged to be complete in 94, 96 and 85% of women with type I, II or III lesions respectively. In order to achieve this, part of the bowel wall had to be resected in 6.3% and part of the posterior vaginal fornix in 13.6% of cases. This risk was associated mainly in type II or III lesions and with larger lesions (P = 0.001). This was not considered as a complication, since all lesions could be repaired endoscopically and since follow-up was uneventful. Complications were one ureter lesion and seven late bowel perforations with periotonitis. Our data did not permit the evaluation as to whether medical pretreatment could improve completeness of surgery or decrease the risk. They revealed, however, that in six of seven women with type III lesions--in whom excision was judged to be complete--no pretreatment had been given and that luteinizing hormone releasing hormone (LHRH) agonist treatment decreased the volume of type II lesions (P = 0.04). In conclusion, complete endoscopic excision could be performed in over 90% of women with deep endometriosis, but required bowel surgery in over 6% of cases. Ureter lesions were rare, but postoperative bowel perforations with periotonitis occurred in 2-3% of cases. Medical pretreatment is advocated since LHRH agonist treatment was shown to shrink the deep endometriotic lesion.

Adult↗