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At least 73 records · Page 4Linked to original sources
PubMed2005

Powerful skin cancer protection by a CPD-photolyase transgene.

BACKGROUND: The high and steadily increasing incidence of ultraviolet-B (UV-B)-induced skin cancer is a problem recognized worldwide. UV introduces different types of damage into the DNA, notably cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs). If unrepaired, these photolesions can give rise to cell death, mutation induction, and onset of carcinogenic events, but the relative contribution of CPDs and 6-4PPs to these biological consequences of UV exposure is hardly known. Because placental mammals have undergone an evolutionary loss of photolyases, repair enzymes that directly split CPDs and 6-4PPs into the respective monomers in a light-dependent and lesion-specific manner, they can only repair UV-induced DNA damage by the elaborate nucleotide excision repair pathway. RESULTS: To assess the relative contribution of CPDs and 6-4PPs to the detrimental effects of UV light, we generated transgenic mice that ubiquitously express CPD-photolyase, 6-4PP-photolyase, or both, thereby allowing rapid light-dependent repair of CPDs and/or 6-4PPs in the skin. We show that the vast majority of (semi)acute responses in the UV-exposed skin (i.e., sunburn, apoptosis, hyperplasia, and mutation induction) can be ascribed to CPDs. Moreover, CPD-photolyase mice, in contrast to 6-4PP-photolyase mice, exhibit superior resistance to sunlight-induced tumorigenesis. CONCLUSIONS: Our data unequivocally identify CPDs as the principal cause of nonmelanoma skin cancer and provide genetic evidence that CPD-photolyase enzymes can be employed as effective tools to combat skin cancer.

Animals↗
PubMed2003

DNA polymerase beta can incorporate ribonucleotides during DNA synthesis of undamaged and CPD-damaged DNA.

Overexpression of the error-prone DNA polymerase beta (Pol beta) has been found to increase spontaneous mutagenesis by competing with the replicative polymerases during DNA replication. Here, we investigate an additional mechanism potentially used by Pol beta to enhance genetic instability via its ability to incorporate ribonucleotides into DNA. By using an in vitro primer extension assay, we show that purified human and calf thymus Pol beta can synthesize up to 8-mer long RNA. Moreover, Pol beta can efficiently incorporate rCTP opposite G in the absence of dCTP and, to a lesser extent, rATP opposite T in the absence of dATP and rGTP opposite C in the absence of dGTP. Recently, Pol beta was shown to catalyze in vitro translesion replication of a thymine cyclobutane pyrimidine dimer (CPD). Here, we investigate if ribonucleotides could be incorporated opposite the CPD damage and modulate the efficiency of the bypass process. We find that all four rNTPs can be incorporated opposite the CPD lesion, and that this process affects translesion synthesis. We discuss how incorporation of ribonucleotides into DNA may contribute to the high frequency of mutagenesis observed in Pol beta up-regulating cells.

Animals↗
PubMed1976

Hemoglobin function in stored blood, XVII. Maintenance of red cell 2,3 DPG (function) and ATP (viability) for six weeks in ACD or CPD-adenine-inosine-methylene blue.

Blood preservatives containing adenine for six week storage have been prepared with inosine and methylene blue at various pH levels in order to maintain, 23-DPG levels for immediate oxygen transport upon transfusion. In one experiment, the adverse effect of a high pH on ATP maintenance was demonstrated in the presence of methylene blue and inosine. In this and other experiments it was clear that ATP was better maintained in low pH preservatives and DPG better maintained in higher pH preservatives. However, 2,3-DPG levels were kept from falling with CPD-adenine-inosine over a wide range of pH values. A CPD-adenine-inosine preservative at a pH 5.8 maintained normal DPG levels for three weeks of storage. A similar preservative but with a pH of 6.6 maintained normal DPG levels for 35 days of storage. It is suggested that if all blood bank units are going to have normal DPG levels for optimal oxygen transport at the time of transfusion then a CPD preservative with a higher pH and/or metabolic nutrients and regulators such as inosine or methylene blue would be required.

Adenine↗
PubMedDate not supplied

The effect of agitation on in vitro metabolism of erythrocytes stored in CPD-adenine.

Agitation of blood stored in plastic containers has been reported to lead to improved posttransfusion survival and it has been found that, in some media, agitation has improved erythrocyte 2,3-diphosphoglycerate (2,3-DPG) levels. Using CPD II media (CPD with 277.5 mM glucose and 2.04 mM adenine), we were not able to identify any improvement in levels of adenosine triphosphate, 2,3-DPG or glucose in whole blood under various agitation conditions when compared with nonagitated control. The 2,3-DPG level was moderately improved through 28 days in the 90 per cent hematocrit packed erythrocytes but the results were not considered to be significantly beneficial to warrant agitation. Thus, the application of agitation to the CPD II blood storage system was of no great benefit in improving metabolic intermediate levels.

Adenine↗
PubMedDate not supplied

Blood storage XXII. Improvement in red blood cell 2,3-DPG levels at six weeks by 20 mM PO4 in CPD-adenine-inosine.

Inorganic phosphate has been known to assist red blood cell maintenance of ATP and in the presence of inosine to assist in the maintenance of 2,3-DPG. High concentrations of phosphate, while helping ATP maintenance, were found to be deleterious to 2,3-DPG maintenance in CPD-adenine preservatives. However, in the presence of inosine, concentrations of phosphate as high as 10 mM were advantageous to 2,3-DPG maintenance. The present study extends the observations on ATP and 2,3-DPG maintenance in CPD-adenine-inosine preservatives from the previous 10 mM to 20 mM phosphate. A high phosphate (20 mM) effect has been seen as improved maintenance of 2,3-DPG levels during the fifth and sixth weeks of storage of whole blood at 4C. This supports the previously reported observation of improved maintenance of 2,3-DPG in a 10 mM phosphate preservative. This is ten times the 2 mM phosphate concentration in CPD-adenine. In the low phosphate preservative (2 mM), 2,3-DPG maintenance is less than that in all of the higher phosphate preservatives after the second week of storage. ATP concentrations in this experiment show good maintenance throughout six weeks of storage.

Adenine↗
PubMedDate not supplied

Blood storage XXIV: red blood cell 2,3-DPG and ATP maintenance for six weeks in CPD-adenine with higher phosphate, pyruvate, and dihydroxyacetone.

The individual and collective effects of various phosphate, pyruvate and dihydroxyacetone concentrations on 2,3-DPG and ATP maintenance during blood storage with CPD-adenine (0.25 mM), were studied. Phosphate concentrations ranged from 2 to 100 mM. Low concentations were best for 2,3-DPG maintenance during the first three weeks, after which there was no difference. ATP concentrations were better maintained by the highest phosphate concentrations in the first week. After the second week the lower concentrations of phosphate were better. With pyruvate 40 and 60 mM were the best for 2,3-DPG levels through six weeks of storage. ATP concentrations were poorest with high pyruvate. Maintenance of 2,3-DPG was above half normal for six weeks of storage in the 60, 80 and 100 mM DHA preservatives. ATP concentrations were best maintained in the preservative lacking DHA. Combinations of phosphate, pyruvate and DHA in concentrations which had been found to be effective when used individually were studied. Best maintenance of 2,3-DPG (above half normal levels) for six weeks was afforded by pyruvate, phosphate and DHA, and by pyruvate and DHA. ATP maintenance was best afforded by CPD-adenine alone and CPD-adenine with pyruvate and phosphate. Pyruvate alone maintained ATP less well and the pyruvate-DHA was worst. Intermediate in maintenance of ATP was the preservative containing pyruvate, phosphate and DHA.

Adenine↗
PubMed1995

Evaluation of a new citrate-acetate-NaCl platelet additive solution for the storage of white cell-reduced platelet concentrates obtained from half-strength CPD pooled buffy coats.

BACKGROUND: A new citrate-acetate-NaCl platelet additive solution, identified as PAS 2, was developed to prepare platelet concentrates (PCs) from pooled 0.5 CPD buffy coats (BCs). STUDY DESIGN AND METHODS: A study was undertaken to evaluate PAS 2 in vitro (n = 8) and in vivo (n = 9) against a commercially available solution (Plasma-Lyte A). In a paired in vitro study, a comparison was made of platelet and white cell concentration; blood gases and bicarbonate; glucose and lactate concentration; total intracellular concentration of adenine nucleotides and beta-thromboglobulin release. RESULTS: A lower platelet yield (p < 0.0001) and a higher beta-thromboglobulin release (p < 0.01) are observed with Plasma-Lyte A. For this reason, half-strength (0.5) CPD was changed to full-strength CPD in the clinical study with Plasma-Lyte A. In a clinical evaluation of nine patients with bone marrow failure, all received PCs with both PAS 2 and Plasma-Lyte A that had a shelf life of at least 4 days. Corrected count increments (CCls) were as follows, on average (95% Cl): the CCl at 1 to 4 hours was 22.4 (95% Cl, 15.2-29.4) for PAS 2 and 24.0 (95% Cl, 16.9-31.2) for Plasma-Lyte A; that at 12 to 24 hours was 11.3 (95% Cl, 4.1-18.4) for PAS 2 and 14.2 (95% Cl, 7.1-21.3) for Plasma-Lyte A; and that at 36 to 48 hours was 4.2 (95% Cl, -3.0-11.3) for PAS 2 and 8.7 (95% Cl, 1.1-16.2) for Plasma-Lyte A. No significant difference between the two solutions was found. CONCLUSIONS: PAS 2 and Plasma-Lyte A make important contributions to platelet transfusion quality improvement and give an excellent CCl even after 4 days of storage.

Acetates↗
PubMed2002

Alkaline CPD and the preservation of RBC 2,3-DPG.

BACKGROUND: Concentrations of 2,3-DPG decline rapidly in the first week of RBC storage because of the low pH of conventional storage solutions. Alkaline additive solutions, which can preserve RBCs for up to 11 weeks, still do not preserve 2,3-DPG because the starting pH is below 7.2. STUDY DESIGN AND METHODS: Alkaline CPD (pH=8.7) was made with trisodium citrate, dextrose, and disodium phosphate. Twelve units of whole blood were collected into heparin and pooled in groups of four units. Each pool was then aliquoted into four units; 63 mL of CPD with pH 5.7, 6.5, 7.5, or 8.7 was added to one unit of each pool, and 300 mL of the alkaline experimental additive solution-76 was added. In Study 2, 12 units were collected into alkaline CPD, pooled in groups of four, aliquoted as described, and stored in four variants of experimental additive solution-76 containing 0, 9, 18, and 27 mM of disodium phosphate. RBC ATP and 2,3-DPG concentrations, intracellular and extracellular pH and phosphate concentrations, hemolysis, and other measures of RBC metabolism and function were measured weekly. RESULTS: RBCs stored in more alkaline conditions made 2,3-DPG, but at the expense of ATP. Concentrations of 2,3-DPG decreased after 2 weeks storage, but ATP concentrations never fully recovered. Providing more phosphate both increased the duration of 2,3-DPG persistence and raised ATP concentrations in the later stages of storage. CONCLUSIONS: Maintaining both 2,3-DPG and ATP requires both high pH and high concentrations of phosphate.

2,3-Diphosphoglycerate↗
PubMed2006

Structure-function analysis of the kinase-CPD domain of yeast tRNA ligase (Trl1) and requirements for complementation of tRNA splicing by a plant Trl1 homolog.

Trl1 is an essential 827 amino acid enzyme that executes the end-healing and end-sealing steps of tRNA splicing in Saccharomyces cerevisiae. Trl1 consists of two domains--an N-terminal ligase component and a C-terminal 5'-kinase/2',3'-cyclic phosphodiesterase (CPD) component--that can function in tRNA splicing in vivo when expressed as separate polypeptides. To understand the structural requirements for the kinase-CPD domain, we performed an alanine scan of 30 amino acids that are conserved in Trl1 homologs from other fungi. We thereby identified four residues (Arg463, His515, Thr675 and Glu741) as essential for activity in vivo. Structure-function relationships at these positions, and at four essential or conditionally essential residues defined previously (Asp425, Arg511, His673 and His777), were clarified by introducing conservative substitutions. Biochemical analysis showed that lethal mutations of Asp425, Arg463, Arg511 and His515 in the kinase module abolished polynucleotide kinase activity in vitro. We report that a recently cloned 1104 amino acid Arabidopsis RNA ligase functions in lieu of yeast Trl1 in vivo and identify essential side chains in the ligase, kinase and CPD modules of the plant enzyme. The plant ligase, like yeast Trl1 but unlike T4 RNA ligase 1, requires a 2'-PO4 end for tRNA splicing in vivo.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1983

Rapid preparation of fresh platelet concentrates from CPD-blood by (mild) acidification.

Two methods of preparation of platelet concentrates (PC) derived from citrate-phosphate-dextrose (CPD) whole blood have been compared: (1) resuspension after having left the PC undisturbed at room temperature for 1 h (according to Mourad), and (2) immediate resuspension of the PC after the centrifugation of a platelet-rich plasma which has been acidified beforehand by the addition of ACD. In vitro platelet yield in acidified (CPD/ACD-)PC was at least equal to and, in cases with a particularly strong postcentrifugal tendency for clumping of platelets, clearly better (p less than 0.05) than in the 'Mourad platelets'. The results show that it is possible to produce PC from fresh CPD whole blood without delay. This may be helpful in clinical situations where freshly prepared PC should be available immediately. A special double bag (Fenwal DFX 733) containing CPD-A in the primary bag and 10 ml of ACD in the satellite bag, allows preparation of PC under these conditions in a closed system.

Blood Platelets↗
PubMed1986

In vitro effect on stored red blood cells and platelets after a 15-hour delayed refrigeration of whole blood prior to component preparation in CPD-AD.

We extended the time of keeping whole blood at 20-24 degrees C to 15 h (overnight) after phlebotomy for preparing platelet concentrates. We have evaluated the in vitro characteristics of platelets and blood cells prepared from whole blood drawn into CPD-AD, an anticoagulant containing 0.4 mM adenine and 1.5 times more dextrose than CPD. We studied in vitro red cell and platelet function of blood cooled either within 4 h after collection or after a 15-hour delay. In vitro platelet function measured as hypotonic shock reaction, aggregation response to ADP and collagen and 14C-serotonin uptake were not significantly different after preparation and after a 5-day storage period. Units held at room temperature for 15 h after blood collection exhibited a level of 2,3-DPG that was 45% of that exhibited by red cells held for 15 h at 1-6 degrees C. All other in vitro parameters of red cell concentrates measured during 35 days of storage were not significantly different. Based on these in vitro data blood drawn into CPD-AD might be kept up to 15 h at room temperature prior to refrigeration in order to prepare platelet concentrates.

2,3-Diphosphoglycerate↗
PubMed2004

Crystal structure of a photolyase bound to a CPD-like DNA lesion after in situ repair.

DNA photolyases use light energy to repair DNA that comprises ultraviolet-induced lesions such as the cis-syn cyclobutane pyrimidine dimers (CPDs). Here we report the crystal structure of a DNA photolyase bound to duplex DNA that is bent by 50 degrees and comprises a synthetic CPD lesion. This CPD lesion is flipped into the active site and split there into two thymines by synchrotron radiation at 100 K. Although photolyases catalyze blue light-driven CPD cleavage only above 200 K, this structure apparently mimics a structural substate during light-driven DNA repair in which back-flipping of the thymines into duplex DNA has not yet taken place.

Base Pairing↗
PubMed1975

Oxygen dissociation after transfusion of blood stored in ACD or CPD solution.

In 20 patients undergoing open-heart surgery, 2,3-diphosphoglycerate (2,3-DPG) concentrations, oxygen affinity of hemoglobin (Po2 at half saturation of hemoglobin with oxygen [P50]), hemoglobin concentration, and pH were measured repeatedly. Measurements were made before and at various times after open-heart surgery and replacement of blood loss with blood stored in acid-citrate-dextrose (ACD) or citrate-phosphate-dextrose (CPD) solutions for less than 72 hours (10 cases per group). Infusion of ACD blood caused P50 and 2,3-DPG concentration to decrease significantly after the operation. The infusion of blood stored in CPD did not significantly increase the oxygen affinity. No significant changes in hemoglobin concentration or pH were observed immediately after the operation in either group. To compensate for the increased oxygen affinity, there must be a rise in cardiac output or more likely a decrease in venous Po2. The transfusion of CPD blood, therefore, is more favorable in terms of oxygen supply, particularly in patients who have had cardiac surgery.

Adult↗
PubMed1978

[Studies of thrombocyte function in CPD blood].

The CPD stabilizer according to Gibson with an addition of 1.25 mMol adeninesulfate and 2.50 mMol guanosine is used in blood storage for better preserving 2.3-bis-phosphoglycerate of erythrocytes. Here platelet-rich CPD plasma was investigated before and during a 3 days storage at 4 degrees C or room temperature with regard to preserving the global thrombocyte function. The latter consists in the ability to seal blood vessels and is tested by means of pressure registration in combined thrombocyte-aggregation-adhesion (DKTA method) as an ability to close the pores of a sieve by adding 10(-5) mM/l of ADP. At room temperature this thrombocyte function is approximately 0 following 3 days of storage in CPD plasma excess without shaking. When stored at 4 degrees C it is preserved to a slight degree. Loss of thrombocyte function will depend on pH, thus being particularly evident at room temperature.

Blood Platelets↗
PubMed2005

The DNA repair enzyme, CPD-photolyase restores the infectivity of UV-damaged fowlpox virus isolated from infected scabs of chickens.

Fowlpox virus (FWPV), an important pathogen of poultry, replicates very efficiently in the featherless areas of skin, and persists in dried and desiccated scabs for prolonged periods. Although the molecular mechanisms underlying the stability of the virus are not completely known, we recently identified the presence of a virus-encoded novel DNA repair enzyme, CPD-photolyase, in FWPV. This enzyme repairs the ultraviolet (UV)-induced pyrimidine dimers, converting them to monomers using photons from white light as a renewable source of energy. In this study, we examined the role of photolyase in the pathogenesis of fowlpox. A comparison of pathogenesis of fowlpox in chickens infected with parental FWPV with that in chickens infected with photolyase-deficient FWPV (Phr(-) FWPV) found no significant differences in terms of replication of virus or formation of secondary lesions. When the virions isolated from infected scabs were exposed to UV light, UV-damaged parental FWPV, unlike Phr(-) FWPV, were rescued through the CPD-photolyase-mediated photoreactivation pathway by at least 48%. However, the mutant virus triggered host's immune response and conferred complete protection against subsequent challenge with virus similar to that conferred by the parental virus. Since the mutant virus is less stable than the parental virus in the infected scabs but is as immunogenic, Phr(-) FWPV might be less persistent in the environment. Furthermore, this particular genetic locus can also be used to insert foreign genes for the development of FWPV recombinant vaccines.

Animals↗
PubMed2000

Refined mapping of the human serotonin transporter (SLC6A4) gene within 17q11 adjacent to the CPD and NF1 genes.

The SLC6A4 gene encodes the serotonin transporter, the target of an important class of antidepressant drugs (serotonin selective reuptake inhibitors). Polymorphisms in the SLC6A4 gene have been reported to be associated with susceptibility to depression and other psychiatric disorders. We have constructed a 1 Mb YAC and PAC contig which harbours both the SLC6A4 and the carboxypeptidase D (CPD) genes. The order of loci within the contig was cen-D17S975-D17S1549-24R-D17S1294-SLC6A4-28L+ ++-(CPD, D17S2009, D17S2004)-D17S2120-ter. Both genes were deleted in one of 17 neurofibromatosis type 1 (NF1) patients carrying submicroscopic NF1 contiguous gene deletions.

Carboxypeptidases↗
PubMedDate not supplied

In vitro metabolism of packed erythrocytes stored in CPD-adenine.

In vitro metabolism of erythrocytes packed at 70 and 90 per cent hematocrits and stored in various CPD-adenine preservatives was studied. It was found that maintenance of acceptable levels of adenosine triphosphate (ATP) for the full 42 days of storage could be accomplished only if glucose levels were doubled from the standard 138.7 mM concentration to 277.5 mM level. If glucose levels were doubled, the amount of adenine could be decreased from 4.07 mM (0.50 mM final concentration) to 2.04 mM (0.25 mM final concentration) with maintenance of ATP at greater than 2.0 mumoles/g Hb. 2,3-diphosphoglycerate concentrations were essentially absent by 21 days in the various media studies. Thus, in vitro levels of ATP appear to be maintained at acceptable levels in a CPD media modified to contain 2 times glucose and 2.04 mM adenine.

Adenine↗