scholarly journals Dissection of the Molecular Defects Caused by Pathogenic Mutations in the DNA Repair Factor XPC

2008 ◽  
Vol 28 (23) ◽  
pp. 7225-7235 ◽  
Author(s):  
Bruno M. Bernardes de Jesus ◽  
Magnar Bjørås ◽  
Frédéric Coin ◽  
Jean Marc Egly
Keyword(s):  
Amino Acid ◽  
Excision Repair ◽  
Biochemical Properties ◽  
Molecular Defects ◽  
Damage Sensing ◽  
Stop Mutation ◽  
Nucleotide Excision ◽  
Repair Factor ◽  
Base Excision ◽  
Repair Defect

ABSTRACT XPC is responsible for DNA damage sensing in nucleotide excision repair (NER). Mutations in XPC lead to a defect in NER and to xeroderma pigmentosum (XP-C). Here, we analyzed the biochemical properties behind mutations found within three patients: one amino acid substitution (P334H, XP1MI, and GM02096), one amino acid incorporation in a conserved domain (697insVal, XP8BE, and GM02249), and a stop mutation (R579St, XP67TMA, and GM14867). Using these mutants, we demonstrated that HR23B stabilizes XPC on DNA and protects it from degradation. XPC recruits the transcription/repair factor TFIIH and stimulates its XPB ATPase activity to initiate damaged DNA opening. In an effort to understand the severity of XP-C phenotypes, we also demonstrated that single mutations in XPC perturb other repair processes, such as base excision repair (e.g., the P334H mutation prevents the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1), thereby leading to a deeper understanding of the molecular repair defect of the XP-C patients.

scholarly journals Mfd Affects Global Transcription and the Physiology of Stressed Bacillus subtilis Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Holly Anne Martin ◽  
Anitha Sundararajan ◽  
Tatiana S. Ermi ◽  
Robert Heron ◽  
Jason Gonzales ◽  
...  
Keyword(s):  
Excision Repair ◽  
Cell Envelope ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Bacterial Physiology ◽  
Cell Functions ◽  
Bacterial Transcription ◽  
Nucleotide Excision ◽  
Repair Factor ◽  
Base Excision

For several decades, Mfd has been studied as the bacterial transcription-coupled repair factor. However, recent observations indicate that this factor influences cell functions beyond DNA repair. Our lab recently described a role for Mfd in disulfide stress that was independent of its function in nucleotide excision repair and base excision repair. Because reports showed that Mfd influenced transcription of single genes, we investigated the global differences in transcription in wild-type and mfd mutant growth-limited cells in the presence and absence of diamide. Surprisingly, we found 1,997 genes differentially expressed in Mfd– cells in the absence of diamide. Using gene knockouts, we investigated the effect of genetic interactions between Mfd and the genes in its regulon on the response to disulfide stress. Interestingly, we found that Mfd interactions were complex and identified additive, epistatic, and suppressor effects in the response to disulfide stress. Pathway enrichment analysis of our RNASeq assay indicated that major biological functions, including translation, endospore formation, pyrimidine metabolism, and motility, were affected by the loss of Mfd. Further, our RNASeq findings correlated with phenotypic changes in growth in minimal media, motility, and sensitivity to antibiotics that target the cell envelope, transcription, and DNA replication. Our results suggest that Mfd has profound effects on the modulation of the transcriptome and on bacterial physiology, particularly in cells experiencing nutritional and oxidative stress.

scholarly journals Mfd affects global transcription and the physiology of stressed Bacillus subtilis cells

2020 ◽  
Author(s):  
Holly Anne Martin ◽  
Anitha Sundararajan ◽  
Tatiana Ermi ◽  
Robert Heron ◽  
Jason Gonzales ◽  
...  
Keyword(s):  
Excision Repair ◽  
Cell Envelope ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Bacterial Physiology ◽  
Cell Functions ◽  
Bacterial Transcription ◽  
Nucleotide Excision ◽  
Repair Factor ◽  
Base Excision

AbstractFor several decades, Mfd has been studied as the bacterial transcription-coupled repair factor. However, recent observations indicate that this factor influences cell functions beyond DNA repair. Our lab recently described a role for Mfd in disulfide stress that was independent of its function in nucleotide excision repair and base excision repair. Because reports showed that Mfd influenced transcription of single genes, we investigated the global differences in transcription in wild-type and mfd mutant growth-limited cells in the presence and absence of diamide. Surprisingly, we found 1,997 genes differentially expressed in Mfd- cells in the absence of diamide. Using gene knockouts, we investigated the effect of genetic interactions between Mfd and the genes in its regulon on the response to disulfide stress. Interestingly, we found that Mfd interactions were complex and identified additive, epistatic, and suppressor effects in the response to disulfide stress. Pathway enrichment analysis of our RNASeq assay indicated that major biological functions, including translation, endospore formation, pyrimidine metabolism, and motility, were affected by the loss of Mfd. Further, our RNASeq findings correlated with phenotypic changes in growth in minimal media, motility, and sensitivity to antibiotics that target the cell envelope, transcription, and DNA replication. Our results suggest that Mfd has profound effects on the modulation of the transcriptome and on bacterial physiology, particularly in cells experiencing nutritional and oxidative stress.

scholarly journals Nucleotide excision repair–initiating proteins bind to oxidative DNA lesions in vivo

2012 ◽  
Vol 199 (7) ◽  
pp. 1037-1046 ◽  
Author(s):  
Hervé Menoni ◽  
Jan H.J. Hoeijmakers ◽  
Wim Vermeulen
Keyword(s):  
Nucleotide Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Dna Lesions ◽  
Dna Damages ◽  
Nucleotide Excision ◽  
Repair Factor ◽  
Base Excision ◽  
Group B

Base excision repair (BER) is the main repair pathway to eliminate abundant oxidative DNA lesions such as 8-oxo-7,8-dihydroguanine. Recent data suggest that the key transcription-coupled nucleotide excision repair factor (TC-NER) Cockayne syndrome group B (CSB) and the global genome NER-initiating factor XPC are implicated in the protection of cells against oxidative DNA damages. Our novel live-cell imaging approach revealed a strong and very rapid recruitment of XPC and CSB to sites of oxidative DNA lesions in living cells. The absence of detectable accumulation of downstream NER factors at the site of local oxidative DNA damage provide the first in vivo indication of the involvement of CSB and XPC in the repair of oxidative DNA lesions independent of the remainder of the NER reaction. Interestingly, CSB exhibited different and transcription-dependent kinetics in the two compartments studied (nucleolus and nucleoplasm), suggesting a direct transcription-dependent involvement of CSB in the repair of oxidative lesions associated with different RNA polymerases but not involving other NER proteins.

Nucleotide Excision Repair Defect Influences Lethality and Mutagenicity Induced by Me-lex, a Sequence-SelectiveN3-Adenine Methylating Agent in the Absence of Base Excision Repair†

Biochemistry ◽  
2004 ◽  
Vol 43 (19) ◽  
pp. 5592-5599 ◽  
Author(s):  
Paola Monti ◽  
Raffaella Iannone ◽  
Paola Campomenosi ◽  
Yari Ciribilli ◽  
Sridhar Varadarajan ◽  
...  
Keyword(s):  
Nucleotide Excision Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Nucleotide Excision ◽  
Base Excision ◽  
Repair Defect

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 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 Abasic Sites in the Transcribed Strand of Yeast DNA Are Removed by Transcription-Coupled Nucleotide Excision Repair

2010 ◽  
Vol 30 (13) ◽  
pp. 3206-3215 ◽  
Author(s):  
Nayun Kim ◽  
Sue Jinks-Robertson
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Genome Integrity ◽  
Genetic Studies ◽  
Abasic Sites ◽  
Dna And Rna ◽  
Nucleotide Excision ◽  
Ap Sites ◽  
Base Excision ◽  
Ap Site

ABSTRACT Abasic (AP) sites are potent blocks to DNA and RNA polymerases, and their repair is essential for maintaining genome integrity. Although AP sites are efficiently dealt with through the base excision repair (BER) pathway, genetic studies suggest that repair also can occur via nucleotide excision repair (NER). The involvement of NER in AP-site removal has been puzzling, however, as this pathway is thought to target only bulky lesions. Here, we examine the repair of AP sites generated when uracil is removed from a highly transcribed gene in yeast. Because uracil is incorporated instead of thymine under these conditions, the position of the resulting AP site is known. Results demonstrate that only AP sites on the transcribed strand are efficient substrates for NER, suggesting the recruitment of the NER machinery by an AP-blocked RNA polymerase. Such transcription-coupled NER of AP sites may explain previously suggested links between the BER pathway and transcription.

scholarly journals Cerebro-Oculo-Facio-Skeletal Syndrome with a Nucleotide Excision–Repair Defect and a Mutated XPD Gene, with Prenatal Diagnosis in a Triplet Pregnancy

2001 ◽  
Vol 69 (2) ◽  
pp. 291-300 ◽  
Author(s):  
John M. Graham ◽  
Kwame Anyane-Yeboa ◽  
Anja Raams ◽  
Esther Appeldoorn ◽  
Wim J. Kleijer ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Triplet Pregnancy ◽  
Nucleotide Excision ◽  
Repair Defect

scholarly journals Plant Organellar DNA Polymerases Evolved Multifunctionality through the Acquisition of Novel Amino Acid Insertions

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1370
Author(s):  
Antolín Peralta-Castro ◽  
Paola L. García-Medel ◽  
Noe Baruch-Torres ◽  
Carlos H. Trasviña-Arenas ◽  
Víctor Juarez-Quintero ◽  
...  
Keyword(s):  
Dna Repair ◽  
Amino Acid ◽  
Dna Replication ◽  
Excision Repair ◽  
Dna Polymerases ◽  
Strand Displacement ◽  
End Joining ◽  
Apparent Contradiction ◽  
Organellar Dna ◽  
Base Excision

The majority of DNA polymerases (DNAPs) are specialized enzymes with specific roles in DNA replication, translesion DNA synthesis (TLS), or DNA repair. The enzymatic characteristics to perform accurate DNA replication are in apparent contradiction with TLS or DNA repair abilities. For instance, replicative DNAPs incorporate nucleotides with high fidelity and processivity, whereas TLS DNAPs are low-fidelity polymerases with distributive nucleotide incorporation. Plant organelles (mitochondria and chloroplast) are replicated by family-A DNA polymerases that are both replicative and TLS DNAPs. Furthermore, plant organellar DNA polymerases from the plant model Arabidopsis thaliana (AtPOLIs) execute repair of double-stranded breaks by microhomology-mediated end-joining and perform Base Excision Repair (BER) using lyase and strand-displacement activities. AtPOLIs harbor three unique insertions in their polymerization domain that are associated with TLS, microhomology-mediated end-joining (MMEJ), strand-displacement, and lyase activities. We postulate that AtPOLIs are able to execute those different functions through the acquisition of these novel amino acid insertions, making them multifunctional enzymes able to participate in DNA replication and DNA repair.

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