scholarly journals Excision of Oxidatively Generated Guanine Lesions by Competitive DNA Repair Pathways

2021 ◽  
Vol 22 (5) ◽  
pp. 2698
Author(s):  
Vladimir Shafirovich ◽  
Nicholas E. Geacintov
Keyword(s):  
Excision Repair ◽  
Dna Lesions ◽  
Dna Templates ◽  
Circular Dna ◽  
Damage Sensing ◽  
Cell Extracts ◽  
Dna Base ◽  
Nucleotide Excision ◽  
Repair Pathways ◽  
Cellular Dna

The base and nucleotide excision repair pathways (BER and NER, respectively) are two major mechanisms that remove DNA lesions formed by the reactions of genotoxic intermediates with cellular DNA. It is generally believed that small non-bulky oxidatively generated DNA base modifications are removed by BER pathways, whereas DNA helix-distorting bulky lesions derived from the attack of chemical carcinogens or UV irradiation are repaired by the NER machinery. However, existing and growing experimental evidence indicates that oxidatively generated DNA lesions can be repaired by competitive BER and NER pathways in human cell extracts and intact human cells. Here, we focus on the interplay and competition of BER and NER pathways in excising oxidatively generated guanine lesions site-specifically positioned in plasmid DNA templates constructed by a gapped-vector technology. These experiments demonstrate a significant enhancement of the NER yields in covalently closed circular DNA plasmids (relative to the same, but linearized form of the same plasmid) harboring certain oxidatively generated guanine lesions. The interplay between the BER and NER pathways that remove oxidatively generated guanine lesions are reviewed and discussed in terms of competitive binding of the BER proteins and the DNA damage-sensing NER factor XPC-RAD23B to these lesions.

scholarly journals Kinetochores Prevent Repair of UV Damage in Saccharomyces cerevisiae Centromeres

2004 ◽  
Vol 24 (16) ◽  
pp. 6907-6918 ◽  
Author(s):  
Christoph Capiaghi ◽  
The Vinh Ho ◽  
Fritz Thoma
Keyword(s):  
Genome Stability ◽  
Excision Repair ◽  
Dna Lesions ◽  
Uv Damage ◽  
Dna Interactions ◽  
Centromere Proteins ◽  
Protein Dna Interactions ◽  
Nucleotide Excision ◽  
Repair Pathways ◽  
Segregation Of Chromosomes

ABSTRACT Centromeres form specialized chromatin structures termed kinetochores which are required for accurate segregation of chromosomes. DNA lesions might disrupt protein-DNA interactions, thereby compromising segregation and genome stability. We show that yeast centromeres are heavily resistant to removal of UV-induced DNA lesions by two different repair systems, photolyase and nucleotide excision repair. Repair resistance persists in G1- and G2/M-arrested cells. Efficient repair was obtained only by disruption of the kinetochore structure in a ndc10-1 mutant, but not in cse4-1 and cbf1Δ mutants. Moreover, UV photofootprinting and DNA repair footprinting showed that centromere proteins cover about 120 bp of the centromere elements CDEII and CDEIII, including 20 bp of flanking CDEIII. Thus, DNA lesions do not appear to disrupt protein-DNA interactions in the centromere. Maintaining a stable kinetochore structure seems to be more important for the cell than immediate removal of DNA lesions. It is conceivable that centromeres are repaired by postreplication repair pathways.

scholarly journals Base Sequence Context Effects on Nucleotide Excision Repair

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Yuqin Cai ◽  
Dinshaw J. Patel ◽  
Suse Broyde ◽  
Nicholas E. Geacintov
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Critical Role ◽  
Model System ◽  
Dna Lesions ◽  
Exact Nature ◽  
Amino Groups ◽  
Environmental Carcinogen ◽  
Cell Extracts ◽  
Nucleotide Excision

Nucleotide excision repair (NER) plays a critical role in maintaining the integrity of the genome when damaged by bulky DNA lesions, since inefficient repair can cause mutations and human diseases notably cancer. The structural properties of DNA lesions that determine their relative susceptibilities to NER are therefore of great interest. As a model system, we have investigated the major mutagenic lesion derived from the environmental carcinogen benzo[a]pyrene (B[a]P), 10S(+)-trans-anti-B[a]P--dG in six different sequence contexts that differ in how the lesion is positioned in relation to nearby guanine amino groups. We have obtained molecular structural data by NMR and MD simulations, bending properties from gel electrophoresis studies, and NER data obtained from human HeLa cell extracts for our six investigated sequence contexts. This model system suggests that disturbed Watson-Crick base pairing is a better recognition signal than a flexible bend, and that these can act in concert to provide an enhanced signal. Steric hinderance between the minor groove-aligned lesion and nearby guanine amino groups determines the exact nature of the disturbances. Both nearest neighbor and more distant neighbor sequence contexts have an impact. Regardless of the exact distortions, we hypothesize that they provide a local thermodynamic destabilization signal for repair.

scholarly journals Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins

2020 ◽  
Vol 43 (1 suppl 1) ◽  
Author(s):  
Namrata Kumar ◽  
Natália C. Moreno ◽  
Bruno C. Feltes ◽  
Carlos FM Menck ◽  
Bennett Van Houten
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Dna Lesions ◽  
Nucleotide Excision ◽  
Repair Pathways

DNA base excision repair and nucleotide excision repair proteins in malignant salivary gland tumors

2021 ◽  
Vol 121 ◽  
pp. 104987
Author(s):  
Fernanda Aragão Felix ◽  
Leorik Pereira da Silva ◽  
Maria Luiza Diniz de Sousa Lopes ◽  
Ana Paula Veras Sobral ◽  
Roseana de Almeida Freitas ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Nucleotide Excision Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Salivary Gland Tumors ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Nucleotide Excision ◽  
Base Excision ◽  
Malignant Salivary Gland Tumors

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 Histone H4 H75E mutation attenuates global genomic and Rad26-independent transcription-coupled nucleotide excision repair

2019 ◽  
Vol 47 (14) ◽  
pp. 7392-7401 ◽  
Author(s):  
Kathiresan Selvam ◽  
Sheikh Arafatur Rahman ◽  
Shisheng Li
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Histone H3 ◽  
Chromatin Accessibility ◽  
Dna Lesions ◽  
Histone H4 ◽  
Uv Sensitivity ◽  
Nucleotide Excision ◽  
Histone Octamers ◽  
Dna Silencing

Abstract Nucleotide excision repair (NER) consists of global genomic NER (GG-NER) and transcription coupled NER (TC-NER) subpathways. In eukaryotic cells, genomic DNA is wrapped around histone octamers (an H3–H4 tetramer and two H2A–H2B dimers) to form nucleosomes, which are well known to profoundly inhibit the access of NER proteins. Through unbiased screening of histone H4 residues in the nucleosomal LRS (loss of ribosomal DNA-silencing) domain, we identified 24 mutations that enhance or decrease UV sensitivity of Saccharomyces cerevisiae cells. The histone H4 H75E mutation, which is largely embedded in the nucleosome and interacts with histone H2B, significantly attenuates GG-NER and Rad26-independent TC-NER but does not affect TC-NER in the presence of Rad26. All the other histone H4 mutations, except for T73F and T73Y that mildly attenuate GG-NER, do not substantially affect GG-NER or TC-NER. The attenuation of GG-NER and Rad26-independent TC-NER by the H4H75E mutation is not due to decreased chromatin accessibility, impaired methylation of histone H3 K79 that is at the center of the LRS domain, or lowered expression of NER proteins. Instead, the attenuation is at least in part due to impaired recruitment of Rad4, the key lesion recognition and verification protein, to chromatin following induction of DNA lesions.

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