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PubMed2000

DNA repair in a yeast origin of replication: contributions of photolyase and nucleotide excision repair.

DNA damage formation and repair are tightly linked to protein-DNA interactions in chromatin. We have used minichromosomes in yeast as chromatin substrates in vivo to investigate how nucleotide excision repair (NER) and repair by DNA-photolyase (photoreactivation) remove pyrimidine dimers from an origin of replication ( ARS1 ). The ARS1 region is nuclease sensitive and flanked by nucleosomes on both sides. Photoreactivation was generally faster than NER at all sites. Site-specific heterogeneity of repair was observed for both pathways. This heterogeneity was different for NER and photoreactivation and it was altered in a minichromosome where ARS1 was transcribed. The results indicate distinct inter-actions of the repair systems with protein complexes bound in the ARS region (ORC, Abf1) and a predominant role of photolyase in CPD repair of an origin of replication.

DNA Damage↗
PubMed1993

Effect of dietary restriction on DNA repair and DNA damage.

Dietary restriction is the only experimental manipulation known to extend lifespan and retard aging in mammals. Therefore, it is a powerful tool for identifying cellular processes that are involved in aging and senescence. Recently, several laboratories have begun to examine the effects of dietary restriction on the integrity of the genome and the ability of cells to repair DNA. In most studies, it was found that the repair of DNA damage, as measured by unscheduled DNA synthesis, was significantly higher in cells isolated from rodents fed calorie-restricted diets compared to cells isolated from rodents fed ad libitum. Dietary restriction also was observed to be associated with a reduction of the levels of certain types of DNA damage; however, preliminary experiments suggest that the effect of dietary restriction on the age-related accumulation of DNA damage depends on the type of DNA damage studied.

Animals↗
PubMed2005

Assessment of human DNA repair (NER) capacity with DNA repair rate (DRR) by comet assay.

OBJECTIVE: Alkaline comet assay was used to evaluate DNA repair (nucleotide excision repair, NER) capacity of human fresh lymphocytes from 12 young healthy non-smokers (6 males and 6 females). METHODS: Lymphocytes were exposed to UV-C (254 nm) at the dose rate of 1.5 J/m2/sec. Novobiocin (NOV) and aphidicolin (APC), DNA repair inhibitors, were utilized to imitate the deficiency of DNA repair capacity at the incision and ligation steps of NER. Lymphocytes from each donor were divided into three grougs: UVC group, UVC plus NOV group, and UVC plus APC group. DNA single strand breaks were detected in UVC irradiated cells incubated for 0, 30, 60, 90, 120, 180, and 240 min after UVC irradiation. DNA repair rate (DRR) served as an indicator of DNA repair capacity. RESULTS: The results indicated that the maximum DNA damage (i.e. maximum tail length) in the UVC group mainly appeared at 90 min. The ranges of DRRs in the UVC group were 62.84%-98.71%. Average DRR value was 81.84%. The DRR difference between males and females was not significant (P < 0.05). However, the average DRR value in the UVC plus NOV group and the UVC plus APC group was 52.98% and 39.57% respectively, which were significantly lower than that in the UVC group (P < 0.01). CONCLUSION: The comet assay is a rapid, simple and sensitive screening test to assess individual DNA repair (NER) capacity. It is suggested that the time to detect DNA single strand breaks in comet assay should include 0 (before UV irradiation), 90 and 240 min after exposure to 1.5 J x m(-2) UVC at least. The DRR, as an indicator, can represent the individual DNA repair capacity in comet assay.

Adult↗
PubMed2000

Structural design of a eukaryotic DNA repair polymerase: DNA polymerase beta.

DNA polymerase beta, the smallest eukaryotic DNA polymerase, is designed to synthesize DNA in short DNA gaps during DNA repair. It is composed of two specialized domains that contribute essential enzymatic activities to base excision repair (BER). Its amino-terminal domain possesses a lyase activity necessary to remove the 5'-deoxyribose phosphate (dRP) intermediate generated during BER. Removal of the dRP moiety is often the rate-limiting step during BER. Failure to remove this group may initiate alternate BER pathways. The larger polymerase domain has nucleotidyl transferase activity. This domain has a modular organization with sub-domains that bind duplex DNA, catalytic metals, and the correct nucleoside triphosphate in a template-dependent manner. X-ray crystal structures of DNA polymerase beta, with and without bound substrates, has inferred that domain, sub-domain, and substrate conformational changes occur upon ligand binding. Many of these conformational changes are distinct from those observed in structures of other DNA polymerases. This review will examine the structural aspects of DNA polymerase beta that facilitate its role in BER.

Crystallography, X-Ray↗
PubMed2005

Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts.

Repairing DNA damage is critical during embryogenesis because development involves sensitive periods of cell proliferation, and abnormal cell growth or death can result in malformations. Knockout mouse experiments have demonstrated that disruption of DNA repair genes results in embryolethality and structural defects. Studies using mid-organogenesis rat embryos showed that DNA repair genes were variably expressed. It is hypothesized that polymorphisms that alter the functionality of DNA repair enzymes may modify the risk of malformations. We conducted a case-control analysis to investigate the relationship between DNA repair gene polymorphisms and the risk of spina bifida and oral clefts. Newborn screening blood spot DNA was obtained for 250 cases (125 spina bifida, 125 oral clefts) identified by the California Birth Defects Monitoring Program, and 350 non-malformation controls identified from birth records. Six single nucleotide polymorphisms of five DNA repair genes representing three distinct repair pathways were interrogated including: XRCC1 (Arg399Gln), APE1 (Asp148Glu), XRCC3 (Thr241Met), hOGG1(Ser326Cys), XPD (Asp312Asn, Lys751Gln). Elevated or decreased odds ratios (OR, adjusted for race/ethnicity) for spina bifida were found for genotypes containing at least one copy of the variant allele for XPD [751Gln, OR = 1.62; 95% confidence interval (CI) = 1.05-2.50] and APE 148 (OR = 0.58; CI = 0.37-0.90). A decreased risk of oral clefts was found for XRCC3 (OR = 0.62; CI = 0.39-0.99) and hOGG1 (326 Cys/Cys, OR = 0.22; CI = 0.06-0.78). This study suggested that polymorphisms of DNA repair genes, representing different major repair pathways, may affect risk of two major birth defects. Future, larger studies, examining additional repair genes, birth defects, and interaction with exposures are recommended.

Alleles↗
PubMed2005

Comparison of functional properties of mammalian DNA polymerase lambda and DNA polymerase beta in reactions of DNA synthesis related to DNA repair.

DNA polymerase lambda (Pol lambda) is a novel enzyme of the family X of DNA polymerases. Pol lambda has some properties in common with DNA polymerase beta (Pol beta). The substrate properties of Pol lambda were compared to Pol beta using DNAs mimicking short-patch (SP) and long-patch (LP) base excision repair (BER) intermediates as well as recessed template primers. In the present work, the influence of several BER proteins such as flap-endonuclease-1 (FEN1), PCNA, and apurinic/apyrimidinic endonuclease-1 (APE1) on the activity of Pol lambda was investigated. Pol lambda is unable to catalyze strand displacement synthesis using nicked DNA, although this enzyme efficiently incorporates a dNMP into a one-nucleotide gap. FEN1 and PCNA stimulate the strand displacement activity of Pol lambda. FEN1 processes nicked DNA, thus removing a barrier to Pol lambda DNA synthesis. It results in a one-nucleotide gapped DNA molecule that is a favorite substrate of Pol lambda. Photocrosslinking and functional assay show that Pol lambda is less efficient than Pol beta in binding to nicked DNA. APE1 has no influence on the strand displacement activity of Pol lambda though it stimulates strand displacement synthesis catalyzed with Pol beta. It is suggested that Pol lambda plays a role in the SP BER rather than contributes to the LP BER pathway.

Animals↗
PubMed1980

Susceptibility to fluorescent light-induced chromatid breaks associated with DNA repair deficiency and malignant transformation in culture.

The increased susceptibility of mouse cells to fluorescent light-induced chromatid damage following their spontaneous malignant transformation in culture could result from loss or inactivation of catalase that decomposes the photoproduct H2O2 or from impaired capacities to repair DNA damage. No consistent change in catalase activity with respect to neoplastic state could be established. To interpret the cytogenetic damage in terms of DNA strand breaks, we determined the incidence of chromatid breaks induced by light exposure during the G1 and late S-G2 phases of the cell cycle in normal and malignant derivatives of a C3H mouse cell line. Chromatid breaks at metaphase following light exposure during G1 would result from DNA strand breaks, cross-links, or base damage, whereas breaks following exposure during late S-G2 would result from single-or double-strand breaks. Both G1 and late S-G2 were susceptible in malignant cells but only G1 in normal. Since caffeine inhibits DNA repair, we compared its effects on light-induced chromatid damage in the normal and malignant cells to assess their DNA repair capacities. Treatment of normal cells with caffeine (50 microgram/ml) directly following five hr of light exposure in G1 increased the chromatid damage to that in malignant cells exposed with or without caffeine. Similarly, treatment of normal cells with caffeine during late S-G2 exposure increased chromatid damage to a level not significantly different from that in malignant cells exposed without caffeine. Caffeine had little influence on chromatid damage in malignant cells. The increased susceptibility of malignant mouse cells to fluorescent light-induced chromatid breaks thus appears to result from impaired capacities to repair DNA damage.

Animals↗
PubMed1999

Photoprotection by topical DNA repair enzymes: molecular correlates of clinical studies.

A new approach to photoprotection is to repair DNA damage after UV exposure. This can be accomplished by delivery of a DNA repair enzyme with specificity to UV-induced cyclobutane pyrimidine dimers into skin by means of specially engineered liposomes. Treatment of DNA-repair-deficient xeroderma pigmentosum patients or skin cancer patients with T4N5 liposome lotion containing such DNA repair liposomes increases the removal of DNA damage in the first few hours after treatment. In these studies, a DNA repair effect was observed in some patients treated with heat-inactivated enzyme. Unexpectedly, it was discovered that the heat-inactivated T4 endonuclease V enzyme refolds and recovers enzymatic activity. These studies demonstrate that measurements of molecular changes induced by biological drugs are useful adjuvants to clinical studies.

Administration, Topical↗
PubMed2002

A variant of the DNA repair gene XRCC3 and risk of squamous cell carcinoma of the head and neck: a case-control analysis.

Individuals differ in their ability to repair DNA damage induced by carcinogens. Studies have shown that polymorphisms in DNA repair genes contribute to individual variation in DNA repair capacity and cancer risk. In a hospital-based case-control study, we tested the hypothesis that a C to T variant (Thr241Met) of DNA repair gene X-ray repair cross-complementing group 3 (XRCC3) is associated with risk of developing squamous cell carcinoma of the head and neck (SCCHN). We genotyped for this variant in 367 non-Hispanic white patients newly diagnosed with SCCHN and 354 frequency-matched cancer-free controls. Compared with the XRCC3 18067CC and 18607CT genotypes, the variant XRCC3 18067TT genotype was associated with a non-statistically significantly increased risk of SCCHN (adjusted odds ratio [ORadj], 1.36; 95% confidence interval [CI], 0.89-2.08), but this risk was significantly increased among female subjects (ORadj 2.23, 95% CI, 1.00-4.98) and current smokers (ORadj, 2.26; 95% CI, 1.02-4.99). These findings suggest that the variant XRCC3 18067TT genotype may not play a major role in the etiology of SCCHN but may contribute to a subset of SCCHN. Larger studies are needed to verify these findings.

Adult↗
PubMed1989

Decreased DNA repair in familial Alzheimer's disease.

Alterations in the capacity of a cell to repair DNA lesions play an important role in a number of human diseases. We and others have demonstrated defective DNA repair of alkylation damage in cells from patients with Alzheimer's disease. It has been hypothesized that this defect is related to the cause of Alzheimer's disease and results in the accumulation of lesions in the central nervous system neurons. One prediction of this hypothesis is that in dominantly inherited Alzheimer's disease, the repair defect will be present in half of the offspring of affected patients long before they develop symptoms of the disease. In order to test the hypothesis that decreased DNA repair is responsible for familial Alzheimer's disease and their at-risk offspring we have studied DNA repair in these individuals after exposure of lymphoblasts to alkylating agents. Our results indicate that cell lines from affected patients repair significantly less damage in 3 h than cell lines from healthy controls. A small number of at-risk individuals were also studied and some of these had lower levels of repair, although more cell lines from individuals in this group must be studied. These findings provide further support for defective DNA repair playing a role in the pathogenesis of Alzheimer's disease.

Adult↗
PubMed1991

[The regulation of DNA repair processes in mammalian cells. II. The repair of DNA radiation damage in NIH 3T3 murine cells transformed by the v-myc oncogene].

The kinetics of repair of the ionizing radiation-induced DNA single- and double-strand breaks in the normal NIH 3T3 mouse cells and in those transformed with virus oncogenes v-myc has been investigated. The incubation of non-transformed cells for 18 hours in serum-free medium results in significant decrease in the rate of the single-strand DNA breaks repair during the first minutes of post-irradiation incubation. This effect is absent in transformed cells. The DNA double-strand breaks repair is more efficient in transformed NIH 3T3 cells as compared to that in the non-transformed ones both after their incubation in the medium with 10% fetal bovine serum or without serum. However, more significant differences in the rate of elimination of these DNA lesions was found in the serum-free medium. Hence, the presence of v-myc sequences in the transformed cells prevented from a decrease in the efficiency of DNA repair due to incubation of cell culture in serum-free medium. These results agree with the assumption that c-myc gene product may be a mediator in regulation of DNA repair by the epidermal growth factor. These data also show that the c-myc gene expression in an important condition providing a high efficiency of the constitutive DNA repair process.

3T3 Cells↗
PubMedDate not supplied

[Mechanisms of the radiation-induced disorder of DNA synthesis. The correlation of biosynthesis, DNA repair and DNA polymerase alpha and beta activity in the bone marrow of rats exposed to gamma quanta and fast neutrons].

A study was made of DNA biosynthesis and repair and alpha- and beta-DNA-polymerase activity in rat bone marrow during the first 24 hours following whole-body irradiation with gamma-quanta and fast neutrons (up to 6 Gy). There was a correlation between the post-irradiation inhibition of DNA biosynthesis, a decrease in DNA-polymerase activity and template reparability. The data obtained permitted to consider the radiation-induced disturbance of DNA biosynthesis and the change in beta-polymerase activity as one of the possible mechanisms of formation of high relative biological effectiveness of neutrons.

Animals↗
PubMed1989

Evidence for unique DNA repair activity encoded by a cloned Serratia marcescens gene: suppression of Escherichia coli mutations that reduce repair of alkylated DNA.

A recombinant plasmid containing a Serratia marcescens DNA repair gene has been analyzed biochemically and genetically in Escherichia coli mutants deficient for repair of alkylated DNA. The cloned gene suppressed sensitivity to methyl methanesulfonate of an E. coli strain deficient in 3-methyladenine DNA glycosylases I and II (i.e., E. coli tag alkA) and two different E. coli recA mutants. Attempts to suppress the methyl methanesulfonate sensitivity of the E. coli recA mutant by using the cloned E. coli tag and alkA genes were not successful. Southern blot analysis did not reveal any homology between the S. marcescens gene and various known E. coli DNA repair genes. Biochemical analysis with the S. marcescens gene showed that the encoded DNA repair protein liberated 3-methyladenine from alkylated DNA, indicating that the DNA repair molecular is an S. marcescens 3-methyladenine DNA glycosylase. The ability to suppress both types of E. coli DNA repair mutations, however, suggests that the S. marcescens gene is a unique bacterial DNA repair gene.

Alkylation↗