Nucleotide Excision Repair: DNA Repair Capacity Variability and Cancer Susceptibility

2013 ◽  
pp. 306-320
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Cancer Susceptibility ◽  
Excision Repair ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Nucleotide Excision

scholarly journals Preliminary Evidence for a Hormetic Effect on DNA Nucleotide Excision Repair in Veterans with Gulf War Illness

2019 ◽  
Vol 185 (1-2) ◽  
pp. e47-e52 ◽  
Author(s):  
Jean J Latimer ◽  
Abdullah Alhamed ◽  
Stefanie Sveiven ◽  
Ali Almutairy ◽  
Nancy G Klimas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Gulf War ◽  
Gulf War Illness ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Persistent Symptoms ◽  
Nucleotide Excision

Abstract Introduction Veterans of the 1991 Gulf War were potentially exposed to a mixture of stress, chemicals and radiation that may have contributed to the persistent symptoms of Gulf War Illness (GWI). The genotoxic effects of some of these exposures are mediated by the DNA nucleotide excision repair (NER) pathway. We hypothesized that individuals with relatively low DNA repair capacity would suffer greater damage from cumulative genotoxic exposures, some of which would persist, causing ongoing problems. Materials and Methods Blood samples were obtained from symptomatic Gulf War veterans and age-matched controls. The unscheduled DNA synthesis assay, a functional measurement of NER capacity, was performed on cultured lymphocytes, and lymphocyte mRNA was extracted and analyzed by sequencing. Results Despite our hypothesis that GWI would be associated with DNA repair deficiency, NER capacity in lymphocytes from affected GWI veterans actually exhibited a significantly elevated level of DNA repair (p = 0.016). Both total gene expression and NER gene expression successfully differentiated individuals with GWI from unaffected controls. The observed functional increase in DNA repair capacity was accompanied by an overexpression of genes in the NER pathway, as determined by RNA sequencing analysis. Conclusion We suggest that the observed elevations in DNA repair capacity and NER gene expression are indicative of a “hormetic,” i.e., induced or adaptive protective response to battlefield exposures. Normally such effects are short-term, but in these individuals this response has resulted in a long-term metabolic shift that may also be responsible for the persistent symptoms of GWI.

scholarly journals Validation of the nucleotide excision repair comet assay on cryopreserved PBMCs to measure inter-individual variation in DNA repair capacity

Mutagenesis ◽  
2012 ◽  
Vol 28 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Alessandra Allione ◽  
Alessia Russo ◽  
Fulvio Ricceri ◽  
Kim Vande Loock ◽  
Simonetta Guarrera ◽  
...  
Keyword(s):  
Dna Repair ◽  
Comet Assay ◽  
Nucleotide Excision Repair ◽  
Individual Variation ◽  
Excision Repair ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Nucleotide Excision

scholarly journals An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair

2008 ◽  
Vol 29 (5) ◽  
pp. 1276-1290 ◽  
Author(s):  
Jaan-Olle Andressoo ◽  
Geert Weeda ◽  
Jan de Wit ◽  
James R. Mitchell ◽  
Rudolf B. Beems ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Xeroderma Pigmentosum ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Cockayne Syndrome ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Neonatal Lethality ◽  
Nucleotide Excision

ABSTRACT Patients carrying mutations in the XPB helicase subunit of the basal transcription and nucleotide excision repair (NER) factor TFIIH display the combined cancer and developmental-progeroid disorder xeroderma pigmentosum/Cockayne syndrome (XPCS). Due to the dual transcription repair role of XPB and the absence of animal models, the underlying molecular mechanisms of XPBXPCS are largely uncharacterized. Here we show that severe alterations in Xpb cause embryonic lethality and that knock-in mice closely mimicking an XPCS patient-derived XPB mutation recapitulate the UV sensitivity typical for XP but fail to show overt CS features unless the DNA repair capacity is further challenged by crossings to the NER-deficient Xpa background. Interestingly, the Xpb XPCS Xpa double mutants display a remarkable interanimal variance, which points to stochastic DNA damage accumulation as an important determinant of clinical diversity in NER syndromes. Furthermore, mice carrying the Xpb XPCS mutation together with a point mutation in the second TFIIH helicase Xpd are healthy at birth but display neonatal lethality, indicating that transcription efficiency is sufficient to permit embryonal development even when both TFIIH helicases are crippled. The double-mutant cells exhibit sensitivity to oxidative stress, suggesting a role for endogenous DNA damage in the onset of XPB-associated CS.

scholarly journals An XPG DNA repair defect causing mutagen hypersensitivity in mouse leukemia L1210 cells.

1995 ◽  
Vol 15 (1) ◽  
pp. 290-297 ◽  
Author(s):  
J A Vilpo ◽  
L M Vilpo ◽  
D E Szymkowski ◽  
A O'Donovan ◽  
R D Wood
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Cisplatin Resistance ◽  
Excision Repair ◽  
Model Systems ◽  
Repair Capacity ◽  
Mouse Leukemia ◽  
L1210 Cells ◽  
Cell Extracts ◽  
Nucleotide Excision

One of the most widely used antitumor drugs is cis-diamminedichloroplatinum(II) (cisplatin), and mechanisms of cisplatin resistance have been investigated in numerous model systems. Many studies have used mouse leukemia L1210/0 as a reference wild-type cell line, and cisplatin-resistant subclones have been derived from it. Increased DNA excision repair capacity is thought to play a key role in the acquired cisplatin resistance, and this has influenced development of drugs for clinical trials. We report here that the L1210/0 line is in fact severely deficient in nucleotide excision repair of damaged DNA in vivo and in vitro. L1210/0 cell extracts could be complemented by extracts from repair-defective human xeroderma pigmentosum (XP) or rodent excision repair cross-complementing (ERCC) mutant cells, except for XPG/ERCC5 mutants. Purified XPG protein could restore repair proficiency to L1210/0 extracts. Expression of mouse XPG mRNA was similar in all L1210 lines studied, suggesting a point mutation or small alteration of XPG in L1210/0 cells. The DNA repair capacity of a cisplatin-resistant subline, L1210/DDP10, is similar to that of type culture collection L1210 cells and to those of other normal mammalian cell lines. Nucleotide excision repair of DNA is thus clearly important in the intrinsic cellular defense against cisplatin. However, in contrast to what is generally believed, enhancement of DNA repair above the normal level in these rodent cells does not appear to be a mechanism of acquired resistance to the drug.

scholarly journals Evidence for the Involvement of DNA Repair Enzyme NEIL1 in Nucleotide Excision Repair of (5′R)- and (5′S)-8,5′-Cyclo-2′-deoxyadenosines

Biochemistry ◽  
2010 ◽  
Vol 49 (6) ◽  
pp. 1053-1055 ◽  
Author(s):  
Pawel Jaruga ◽  
Yan Xiao ◽  
Vladimir Vartanian ◽  
R. Stephen Lloyd ◽  
Miral Dizdaroglu
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Repair Enzyme ◽  
Nucleotide Excision

Stable and specific association between the yeast recombination and DNA repair proteins RAD1 and RAD10 in vitro

1992 ◽  
Vol 12 (7) ◽  
pp. 3041-3049
Author(s):  
L Bardwell ◽  
A J Cooper ◽  
E C Friedberg
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Specific Interaction ◽  
Mitotic Recombination ◽  
Nucleotide Excision ◽  
Specific Association ◽  
Recombination Pathway ◽  
Cloned Gene

The RAD1 and RAD10 genes of Saccharomyces cerevisiae are two of at least seven genes which are known to be required for damage-specific recognition and/or damage-specific incision of DNA during nucleotide excision repair. RAD1 and RAD10 are also involved in a specialized mitotic recombination pathway. We have previously reported the purification of the RAD10 protein to homogeneity (L. Bardwell, H. Burtscher, W. A. Weiss, C. M. Nicolet, and E. C. Friedberg, Biochemistry 29:3119-3126, 1990). In the present studies we show that the RAD1 protein, produced by in vitro transcription and translation of the cloned gene, specifically coimmunoprecipitates with the RAD10 protein translated in vitro or purified from yeast. Conversely, in vitro-translated RAD10 protein specifically coimmunoprecipitates with the RAD1 protein. The sites of this stable and specific interaction have been mapped to the C-terminal regions of both polypeptides. This portion of RAD10 protein is evolutionarily conserved. These results are the first biochemical evidence of a specific association between any eukaryotic proteins genetically identified as belonging to a recombination or DNA repair pathway and suggest that the RAD1 and RAD10 proteins act at the same or consecutive biochemical steps in both nucleotide excision repair and mitotic recombination.

scholarly journals Structural basis of TFIIH activation for nucleotide excision repair

2019 ◽  
Author(s):  
Goran Kokic ◽  
Aleksandar Chernev ◽  
Dimitry Tegunov ◽  
Christian Dienemann ◽  
Henning Urlaub ◽  
...  
Keyword(s):  
Dna Repair ◽  
Transcription Factor ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Dna Lesions ◽  
Structural Basis ◽  
Disease Mutations ◽  
Mechanistic Analysis ◽  
Nucleotide Excision ◽  
Dna Complex

AbstractGenomes are constantly threatened by DNA damage, but cells can remove a large variety of DNA lesions by nucleotide excision repair (NER)1. Mutations in NER factors compromise cellular fitness and cause human diseases such as Xeroderma pigmentosum (XP), Cockayne syndrome and trichothiodystrophy2,3. The NER machinery is built around the multisubunit transcription factor IIH (TFIIH), which opens the DNA repair bubble, scans for the lesion, and coordinates excision of the damaged DNA single strand fragment1,4. TFIIH consists of a kinase module and a core module that contains the ATPases XPB and XPD5. Here we prepare recombinant human TFIIH and show that XPB and XPD are stimulated by the additional NER factors XPA and XPG, respectively. We then determine the cryo-electron microscopy structure of the human core TFIIH-XPA-DNA complex at 3.6 Å resolution. The structure represents the lesion-scanning intermediate on the NER pathway and rationalizes the distinct phenotypes of disease mutations. It reveals that XPB and XPD bind double- and single-stranded DNA, respectively, consistent with their translocase and helicase activities. XPA forms a bridge between XPB and XPD, and retains the DNA at the 5’-edge of the repair bubble. Biochemical data and comparisons with prior structures6,7 explain how XPA and XPG can switch TFIIH from a transcription factor to a DNA repair factor. During transcription, the kinase module inhibits the repair helicase XPD8. For DNA repair, XPA dramatically rearranges the core TFIIH structure, which reorients the ATPases, releases the kinase module and displaces a ‘plug’ element from the DNA-binding pore in XPD. This enables XPD to move by ~80 Å, engage with DNA, and scan for the lesion in a XPG-stimulated manner. Our results provide the basis for a detailed mechanistic analysis of the NER mechanism.

scholarly journals An optimized comet-based in vitro DNA repair assay to assess base and nucleotide excision repair activity

2020 ◽  
Vol 15 (12) ◽  
pp. 3844-3878
Author(s):  
Sona Vodenkova ◽  
Amaya Azqueta ◽  
Andrew Collins ◽  
Maria Dusinska ◽  
Isabel Gaivão ◽  
...  
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Nucleotide Excision ◽  
Repair Activity

scholarly journals Growth Retardation, Early Death, and DNA Repair Defects in Mice Deficient for the Nucleotide Excision Repair Enzyme XPF

2004 ◽  
Vol 24 (3) ◽  
pp. 1200-1205 ◽  
Author(s):  
Ming Tian ◽  
Reiko Shinkura ◽  
Nobuhiko Shinkura ◽  
Frederick W. Alt
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Uv Irradiation ◽  
Excision Repair ◽  
Genetic Defect ◽  
Growth Defect ◽  
Human Genetic Disease ◽  
Nucleotide Excision ◽  
Deficient Mice

ABSTRACT Xeroderma pigmentosum (XP) is a human genetic disease which is caused by defects in nucleotide excision repair. Since this repair pathway is responsible for removing UV irradiation-induced damage to DNA, XP patients are hypersensitive to sunlight and are prone to develop skin cancer. Based on the underlying genetic defect, the disease can be divided into the seven complementation groups XPA through XPG. XPF, in association with ERCC1, constitutes a structure-specific endonuclease that makes an incision 5′ to the photodamage. XPF-ERCC1 has also been implicated in both removal of interstrand DNA cross-links and homology-mediated recombination and in immunoglobulin class switch recombination (CSR). To study the function of XPF in vivo, we inactivated the XPF gene in mice. XPF-deficient mice showed a severe postnatal growth defect and died approximately 3 weeks after birth. Histological examination revealed that the liver of mutant animals contained abnormal cells with enlarged nuclei. Furthermore, embryonic fibroblasts defective in XPF are hypersensitive to UV irradiation and mitomycin C treatment. No defect in CSR was detected, suggesting that the nuclease is dispensable for this recombination process. These phenotypes are identical to those exhibited by the ERCC1-deficient mice, consistent with the functional association of the two proteins. The complex phenotype suggests that XPF-ERCC1 is involved in multiple DNA repair processes.

Sign in / Sign up

Export Citation Format

Share Document