scholarly journals Role and Regulation of the RECQL4 Family during Genomic Integrity Maintenance

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1919
Author(s):  
Thong T. Luong ◽  
Kara A. Bernstein
Keyword(s):  
Dna Repair ◽  
Excision Repair ◽  
Genetic Diseases ◽  
Genomic Stability ◽  
Strand Break ◽  
Developmental Defects ◽  
Dna Helicases ◽  
Nucleotide Excision ◽  
Evolutionarily Conserved ◽  
Base Excision

RECQL4 is a member of the evolutionarily conserved RecQ family of 3’ to 5’ DNA helicases. RECQL4 is critical for maintaining genomic stability through its functions in DNA repair, recombination, and replication. Unlike many DNA repair proteins, RECQL4 has unique functions in many of the central DNA repair pathways such as replication, telomere, double-strand break repair, base excision repair, mitochondrial maintenance, nucleotide excision repair, and crosslink repair. Consistent with these diverse roles, mutations in RECQL4 are associated with three distinct genetic diseases, which are characterized by developmental defects and/or cancer predisposition. In this review, we provide an overview of the roles and regulation of RECQL4 during maintenance of genome homeostasis.

scholarly journals True Lies: The Double Life of the Nucleotide Excision Repair Factors in Transcription and DNA Repair

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Nicolas Le May ◽  
Jean-Marc Egly ◽  
Frédéric Coin
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Genetic Disorders ◽  
Accelerated Aging ◽  
Synthesis Process ◽  
Developmental Defects ◽  
Pyrimidine Dimers ◽  
Nucleotide Excision ◽  
Active Genes

Nucleotide excision repair (NER) is a major DNA repair pathway in eukaryotic cells. NER removes structurally diverse lesions such as pyrimidine dimers, arising upon UV irradiation or bulky chemical adducts, arising upon exposure to carcinogens and some chemotherapeutic drugs. NER defects lead to three genetic disorders that result in predisposition to cancers, accelerated aging, neurological and developmental defects. During NER, more than 30 polypeptides cooperate to recognize, incise, and excise a damaged oligonucleotide from the genomic DNA. Recent papers reveal an additional and unexpected role for the NER factors. In the absence of a genotoxic attack, the promoters of RNA polymerases I- and II-dependent genes recruit XPA, XPC, XPG, and XPF to initiate gene expression. A model that includes the growth arrest and DNA damage 45αprotein (Gadd45α) and the NER factors, in order to maintain the promoter of active genes under a hypomethylated state, has been proposed but remains controversial. This paper focuses on the double life of the NER factors in DNA repair and transcription and describes the possible roles of these factors in the RNA synthesis process.

scholarly journals Contribution of Base Excision Repair, Nucleotide Excision Repair, and DNA Recombination to Alkylation Resistance of the Fission Yeast Schizosaccharomyces pombe

2000 ◽  
Vol 182 (8) ◽  
pp. 2104-2112 ◽  
Author(s):  
Asli Memisoglu ◽  
Leona Samson
Keyword(s):  
Dna Repair ◽  
Schizosaccharomyces Pombe ◽  
Nucleotide Excision Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Recombination ◽  
Nucleotide Excision ◽  
Repair Pathways ◽  
Base Excision

ABSTRACT DNA damage is unavoidable, and organisms across the evolutionary spectrum possess DNA repair pathways that are critical for cell viability and genomic stability. To understand the role of base excision repair (BER) in protecting eukaryotic cells against alkylating agents, we generated Schizosaccharomyces pombe strains mutant for the mag1 3-methyladenine DNA glycosylase gene. We report that S. pombe mag1 mutants have only a slightly increased sensitivity to methylation damage, suggesting that Mag1-initiated BER plays a surprisingly minor role in alkylation resistance in this organism. We go on to show that other DNA repair pathways play a larger role than BER in alkylation resistance. Mutations in genes involved in nucleotide excision repair (rad13) and recombinational repair (rhp51) are much more alkylation sensitive thanmag1 mutants. In addition, S. pombe mutant for the flap endonuclease rad2 gene, whose precise function in DNA repair is unclear, were also more alkylation sensitive thanmag1 mutants. Further, mag1 andrad13 interact synergistically for alkylation resistance, and mag1 and rhp51 display a surprisingly complex genetic interaction. A model for the role of BER in the generation of alkylation-induced DNA strand breaks in S. pombe is discussed.

DNA repair and genomic stability

2019 ◽  
pp. 173-183
Author(s):  
John C. Lucchesi
Keyword(s):  
Excision Repair ◽  
Strand Break ◽  
End Joining ◽  
Single Strand Break ◽  
Dna Mismatch ◽  
Single Strand Break Repair ◽  
Pyrimidine Dimers ◽  
Nucleotide Excision ◽  
Base Excision ◽  
Non Homologous End Joining

A number of pathways have evolved in order to repair DNA. Mismatch repair (MMR) operates when an improper nucleotide is used or when an insertion or deletion occurs during replication. Nucleotide excision repair (NER) repairs damage that distorts the DNA helix such as the presence of pyrimidine dimers induced by ultraviolet light. Base excision repair (BER) removes damaged or altered DNA bases that do not result in a conformational change in the chromatin. Single-strand break repair (SSBR) uses the same enzymatic steps as BER. Double-strand break (DSB) repair can involve either non-homologous end-joining (NHEJ) or homologous recombination (HR). In NHEJ, the broken DNA ends are joined directly. HR requires that one of the strands of the broken DNA molecule participates in the strand invasion of the sister chromatid. The site of the DSB must be modified to allow access to the repair machinery. This modification involves remodeling complexes, as well as histone-modifying enzymes.

scholarly journals Distribution of DNA repair-related ESTs in sugarcane

2001 ◽  
Vol 24 (1-4) ◽  
pp. 141-146 ◽  
Author(s):  
W.C. Lima ◽  
R. Medina-Silva ◽  
R.S. Galhardo ◽  
C.F.M. Menck
Keyword(s):  
Dna Repair ◽  
Biochemical Analysis ◽  
Excision Repair ◽  
Expression Patterns ◽  
Cdna Libraries ◽  
Nucleotide Excision ◽  
Exogenous Agents ◽  
Base Excision ◽  
Repair Genes ◽  
Expressed Sequence

DNA repair pathways are necessary to maintain the proper genomic stability and ensure the survival of the organism, protecting it against the damaging effects of endogenous and exogenous agents. In this work, we made an analysis of the expression patterns of DNA repair-related genes in sugarcane, by determining the EST (expressed sequence tags) distribution in the different cDNA libraries of the SUCEST transcriptome project. Three different pathways - photoreactivation, base excision repair and nucleotide excision repair - were investigated by employing known DNA repair proteins as probes to identify homologous ESTs in sugarcane, by means of computer similarity search. The results showed that DNA repair genes may have differential expressions in tissues, depending on the pathway studied. These in silico data provide important clues on the potential variation of gene expression, to be confirmed by direct biochemical analysis.

scholarly journals DNA Repair and Transcriptional Deficiencies Caused by Mutations in the Drosophila p52 Subunit of TFIIH Generate Developmental Defects and Chromosome Fragility

2007 ◽  
Vol 27 (10) ◽  
pp. 3640-3650 ◽  
Author(s):  
Mariana Fregoso ◽  
Jean-Philippe Lainé ◽  
Javier Aguilar-Fuentes ◽  
Vincent Mocquet ◽  
Enrique Reynaud ◽  
...  
Keyword(s):  
Dna Repair ◽  
Biochemical Analysis ◽  
Excision Repair ◽  
Uv Light ◽  
Point Mutations ◽  
Developmental Defects ◽  
Nucleotide Excision ◽  
Chromosome Fragility ◽  
Repair Factor

ABSTRACT The transcription and DNA repair factor TFIIH is composed of 10 subunits. Mutations in the XPB, XPD, and p8 subunits are genetically linked to human diseases, including cancer. However, no reports of mutations in other TFIIH subunits have been reported in higher eukaryotes. Here, we analyze at genetic, molecular, and biochemical levels the Drosophila melanogaster p52 (DMP52) subunit of TFIIH. We found that DMP52 is encoded by the gene marionette in Drosophila and that a defective DMP52 produces UV light-sensitive flies and specific phenotypes during development: organisms are smaller than their wild-type siblings and present tumors and chromosomal instability. The human homologue of DMP52 partially rescues some of these phenotypes. Some of the defects observed in the fly caused by mutations in DMP52 generate trichothiodystrophy and cancer-like phenotypes. Biochemical analysis of DMP52 point mutations introduced in human p52 at positions homologous to those of defects in DMP52 destabilize the interaction between p52 and XPB, another TFIIH subunit, thus compromising the assembly of the complex. This study significantly extends the role of p52 in regulating XPB ATPase activity and, consequently, both its transcriptional and nucleotide excision repair functions.

scholarly journals Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

2012 ◽  
Vol 287 (15) ◽  
pp. 12379-12386 ◽  
Author(s):  
Hsiang-Tsui Wang ◽  
Yu Hu ◽  
Dan Tong ◽  
Jian Huang ◽  
Liya Gu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Lung Fibroblasts ◽  
Proteasome Inhibitor Mg132 ◽  
Nucleotide Excision ◽  
Bronchial Epithelia ◽  
Normal Human ◽  
Induced Mutagenesis ◽  
Base Excision

Acrolein (Acr), a ubiquitous environmental contaminant, is a human carcinogen. Acr can react with DNA to form mutagenic α- and γ-hydroxy-1, N2-cyclic propano-2′-deoxyguanosine adducts (α-OH-Acr-dG and γ-OH-Acr-dG). We demonstrate here that Acr-dG adducts can be efficiently repaired by the nucleotide excision repair (NER) pathway in normal human bronchial epithelia (NHBE) and lung fibroblasts (NHLF). However, the same adducts were poorly processed in cell lysates isolated from Acr-treated NHBE and NHLF, suggesting that Acr inhibits NER. In addition, we show that Acr treatment also inhibits base excision repair and mismatch repair. Although Acr does not change the expression of XPA, XPC, hOGG1, PMS2 or MLH1 genes, it causes a reduction of XPA, XPC, hOGG1, PMS2, and MLH1 proteins; this effect, however, can be neutralized by the proteasome inhibitor MG132. Acr treatment further enhances both bulky and oxidative DNA damage-induced mutagenesis. These results indicate that Acr not only damages DNA but can also modify DNA repair proteins and further causes degradation of these modified repair proteins. We propose that these two detrimental effects contribute to Acr mutagenicity and carcinogenicity.

Ubiquitin and SUMO signalling in DNA repair

2010 ◽  
Vol 38 (1) ◽  
pp. 116-131 ◽  
Author(s):  
Timothy M. Thomson ◽  
Marta Guerra-Rebollo
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Translesion Synthesis ◽  
Strand Break ◽  
Cross Link ◽  
Post Translational Modifications ◽  
Nucleotide Excision ◽  
Specific Proteins ◽  
Modified Proteins

The repair of lesions and gaps in DNA follows different pathways, each mediated by specific proteins and complexes. Post-translational modifications in many of these proteins govern their activities and interactions, ultimately determining whether a particular pathway is followed. Prominent among these modifications are the addition of phosphate or ubiquitin (and ubiquitin-like) moieties that confer new binding surfaces and conformational states on the modified proteins. The present review summarizes some of consequences of ubiquitin and ubiquitin-like modifications and interactions that regulate nucleotide excision repair, translesion synthesis, double-strand break repair and interstrand cross-link repair, with the discussion of relevant examples in each pathway.

scholarly journals Elevated glucose increases genomic instability by inhibiting nucleotide excision repair

2021 ◽  
Vol 4 (10) ◽  
pp. e202101159
Author(s):  
Alexandra K Ciminera ◽  
Sarah C Shuck ◽  
John Termini
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Hypoxia Inducible Factor ◽  
Strand Break ◽  
Strand Breaks ◽  
Nucleotide Excision ◽  
Elevated Glucose ◽  
Dna Strand

We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct N2-(1-carboxyethyl)-2ʹ-deoxyguanosine (CEdG). Glycation stress in NER-competent cells yielded single-strand breaks accompanied by ATR activation, γH2AX induction, and enhanced non-homologous end-joining and homology-directed repair. In NER-deficient cells, glycation stress activated ATM/ATR/H2AX, consistent with double-strand break formation. Elevated glucose inhibited DNA repair by attenuating hypoxia-inducible factor-1α–mediated transcription of NER genes via enhanced 2-ketoglutarate–dependent prolyl hydroxylase (PHD) activity. PHD inhibition enhanced transcription of NER genes and facilitated CEdG repair. These results are consistent with a role for hyperglycemia in promoting genomic instability as a potential mechanism for increasing cancer risk in metabolic disease. Because of the pleiotropic functions of many NER genes beyond DNA repair, these results may have broader implications for cellular pathophysiology.

scholarly journals Exploiting DNA repair defects in triple negative breast cancer to improve cell killing

2020 ◽  
Vol 12 ◽  
pp. 175883592095835 ◽  
Author(s):  
Kevin J. Lee ◽  
Elise Mann ◽  
Griffin Wright ◽  
Cortt G. Piett ◽  
Zachary D. Nagel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Triple Negative ◽  
Excision Repair ◽  
Molecular Targets ◽  
Preclinical Models ◽  
Nucleotide Excision ◽  
Damage Response ◽  
Base Excision

Background: The lack of molecular targets for triple negative breast cancer (TNBC) has limited treatment options and reduced survivorship. Identifying new molecular targets may help improve patient survival and decrease recurrence and metastasis. As DNA repair defects are prevalent in breast cancer, we evaluated the expression and repair capacities of DNA repair proteins in preclinical models. Methods: DNA repair capacity was analyzed in four TNBC cell lines, MDA-MB-157 (MDA-157), MDA-MB-231 (MDA-231), MDA-MB-468 (MDA-468), and HCC1806, using fluorescence multiplex host cell reactivation (FM-HCR) assays. Expression of DNA repair genes was analyzed with RNA-seq, and protein expression was evaluated with immunoblot. Responses to the combination of DNA damage response inhibitors and primary chemotherapy drugs doxorubicin or carboplatin were evaluated in the cell lines. Results: Defects in base excision and nucleotide excision repair were observed in preclinical TNBC models. Gene expression analysis showed a limited correlation between these defects. Loss in protein expression was a better indicator of these DNA repair defects. Over-expression of PARP1, XRCC1, RPA, DDB1, and ERCC1 was observed in TNBC preclinical models, and likely contributed to altered sensitivity to chemotherapy and DNA damage response (DDR) inhibitors. Improved cell killing was achieved when primary therapy was combined with DDR inhibitors for ATM, ATR, or CHK1. Conclusion: Base excision and nucleotide excision repair pathways may offer new molecular targets for TNBC. The functional status of DNA repair pathways should be considered when evaluating new therapies and may improve the targeting for primary and combination therapies with DDR inhibitors.

scholarly journals Regulation of DNA repair in serum-stimulated xeroderma pigmentosum cells.

1984 ◽  
Vol 99 (4) ◽  
pp. 1275-1281 ◽  
Author(s):  
P K Gupta ◽  
M A Sirover
Keyword(s):  
Dna Repair ◽  
Dna Synthesis ◽  
Nucleotide Excision Repair ◽  
Base Excision Repair ◽  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Nucleotide Excision ◽  
Normal Human ◽  
Complementation Groups ◽  
Base Excision

The regulation of DNA repair during serum stimulation of quiescent cells was examined in normal human cells, in fibroblasts from three xeroderma pigmentosum complementation groups (A, C, and D), in xeroderma pigmentosum variant cells, and in ataxia telangiectasia cells. The regulation of nucleotide excision repair was examined by exposing cells to ultraviolet irradiation at discrete intervals after cell stimulation. Similarly, base excision repair was quantitated after exposure to methylmethane sulfonate. WI-38 normal human diploid fibroblasts, xeroderma pigmentosum variant cells, as well as ataxia telangiectasia cells enhanced their capacity for both nucleotide excision repair and for base excision repair prior to their enhancement of DNA synthesis. Further, in each cell strain, the base excision repair enzyme uracil DNA glycosylase was increased prior to the induction of DNA polymerase using the identical cells to quantitate each activity. In contrast, each of the three xeroderma complementation groups that were examined failed to increase their capacity for nucleotide excision repair above basal levels at any interval examined. This result was observed using either unscheduled DNA synthesis in the presence of 10 mM hydroxyurea or using repair replication in the absence of hydroxyurea to quantitate DNA repair. However, each of the three complementation groups normally regulated the enhancement of base excision repair after methylmethane sulfonate exposure and each induced the uracil DNA glycosylase prior to DNA synthesis. These results suggest that there may be a relationship between the sensitivity of xeroderma pigmentosum cells from each complementation group to specific DNA damaging agents and their inability to regulate nucleotide excision repair during cell stimulation.

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