scholarly journals B Lymphocytes of Xeroderma Pigmentosum or Cockayne Syndrome Patients with Inherited Defects in Nucleotide Excision Repair Are Fully Capable of Somatic Hypermutation of Immunoglobulin Genes

1997 ◽  
Vol 186 (3) ◽  
pp. 413-419 ◽  
Author(s):  
Nayun Kim ◽  
Karen Kage ◽  
Fumihiko Matsuda ◽  
Marie-Paule Lefranc ◽  
Ursula Storb
Keyword(s):  
Dna Repair ◽  
B Cells ◽  
Nucleotide Excision Repair ◽  
Somatic Mutation ◽  
Transcription Initiation ◽  
Somatic Hypermutation ◽  
Excision Repair ◽  
Point Mutations ◽  
Nucleotide Excision ◽  
Gene Switch

Recent experiments have strongly suggested that the process of somatic mutation is linked to transcription initiation. It was postulated that a mutator factor loads onto the RNA polymerase and, during elongation, causes transcriptional arrest that activates DNA repair, thus occasionally causing errors in the DNA sequence. We report the analysis of the role of one of the known DNA repair systems, nucleotide excision repair (NER), in somatic mutation. Epstein–Barrvirus-transformed B cells from patients with defects in NER (XP-B, XP-D, XP-V, and CS-A) were studied. Their heavy and light chain genes show a high frequency of point mutations in the variable (V), but not in the constant (C) regions. This suggests that these B cells can undergo somatic hypermutation despite significant defects in NER. Thus, it is doubtful that NER is an essential part of the mechanism of somatic hypermutation of Ig genes. As an aside, NER seems also not involved in Ig gene switch recombination.

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 Nucleotide excision repair syndromes: molecular basis and clinical symptoms

1995 ◽  
Vol 347 (1319) ◽  
pp. 75-81 ◽  
Keyword(s):  
Nucleotide Excision Repair ◽  
Transcription Initiation ◽  
Clinical Symptoms ◽  
Excision Repair ◽  
Complementation Group ◽  
Molecular Defect ◽  
Cockayne's Syndrome ◽  
Nucleotide Excision ◽  
Group B ◽  
Deficiency Diseases

The phenotypic consequences of a nucleotide excision repair (NER) defect in man are apparent from three distinct inborn diseases characterized by hypersensitivity of the skin to ultraviolet light and a remarkable clinical and genetic heterogeneity. These are the prototype repair syndrome, xeroderma pigmentosum (XP) (seven genetic complementation groups, designated XP-A to XP-G), Cockayne’s syndrome (two groups: CS-A and CS-B) and PIBIDS, a peculiar photosensitive form of the brittle hair disease trichothiodystrophy (TTD, at least two groups of which one equivalent to XP-D). To investigate the mechanism of NER and to resolve the molecular defect in these NER deficiency diseases we have focused on the cloning and characterization of human DNA repair genes. One of the genes that we cloned is ERCC3 . It specifies a chromatin binding helicase. Transfection and microinjection experiments demonstrated that mutations in ERCC3 are responsible for XP complementation group B, a very rare form of XP that is simultaneously associated with Cockayne’s syndrome (CS). The ERCC3 protein was found to be part of a multiprotein complex (TFIIH) required for transcription initiation of most structural genes and for NER . This defines the additional, hitherto unknown vital function of the gene. This ERCC3 gene and several other ner genes involved in transcription initiation will be discussed.

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.

scholarly journals TAp63γ enhances nucleotide excision repair through transcriptional regulation of DNA repair genes

DNA Repair ◽  
2012 ◽  
Vol 11 (2) ◽  
pp. 167-176 ◽  
Author(s):  
Juan Liu ◽  
Meihua Lin ◽  
Cen Zhang ◽  
Duoduo Wang ◽  
Zhaohui Feng ◽  
...  
Keyword(s):  
Dna Repair ◽  
Transcriptional Regulation ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Dna Repair Genes ◽  
Nucleotide Excision ◽  
Repair Genes
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