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- Cohen, Rotem, et al.
(author)
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Ribonucleotide reductase from Fusarium oxysporum does not Respond to DNA replication stress
- 2019
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In: DNA Repair. - : Elsevier. - 1568-7864 .- 1568-7856. ; 83
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Journal article (peer-reviewed)abstract
- Ribonucleotide reductase (RNR) catalyzes the rate limiting step in dNTP biosynthesis and is tightly regulated at the transcription and activity levels. One of the best characterized responses of yeast to DNA damage is up-regulation of RNR transcription and activity and consequently, elevation of the dNTP pools. Hydroxyurea is a universal inhibitor of RNR that causes S phase arrest. It is used in the clinic to treat certain types of cancers. Here we studied the response of the fungal plant pathogen Fusarium oxysporum to hydroxyurea in order to generate hypotheses that can be used in the future in development of a new class of pesticides. F. oxysporum causes severe damage to more than 100 agricultural crops and specifically threatens banana cultivation world-wide. Although the recovery of F. oxysporum from transient hydroxyurea exposure was similar to the one of Saccharomyces cerevisiae, colony formation was strongly inhibited in F. oxysporum in comparison with S. cerevisiae. As expected, genomic and phosphoproteomic analyses of F. oxysporum conidia (spores) exposed to hydroxyurea showed hallmarks of DNA replication perturbation and activation of recombination. Unexpectedly and strikingly, RNR was not induced by either hydroxyurea or the DNA-damaging agent methyl methanesulfonate as determined at the RNA and protein levels. Consequently, dNTP concentrations were significantly reduced, even in response to a low dose of hydroxyurea. Methyl methanesulfonate treatment did not induce dNTP pools in F. oxysporum, in contrast to the response of RNR and dNTP pools to DNA damage and hydroxyurea in several tested organisms. Our results are important because the lack of a feedback mechanism to increase RNR expression in F. oxysporum is expected to sensitize the pathogen to a fungal-specific ribonucleotide inhibitor. The potential impact of our observations on F. oxysporum genome stability and genome evolution is discussed.
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- Farnebo, Lovisa, et al.
(author)
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DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck
- 2015
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In: DNA Repair. - : Elsevier. - 1568-7864 .- 1568-7856. ; 31, s. 64-72
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Journal article (peer-reviewed)abstract
- Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors with a high rate of early recurrences, second primary tumors, and mortality. Despite advances in diagnosis and treatment over the past decades, the overall 5-year survival rate remains around 50%. Since the head-and neck-region is continuously exposed to potentially DNA-damaging exogenous and endogenous factors, it is reasonable to expect that the DNA repair genes play a part in the development, progression, and outcome of HNSCC. The aim of this study was to investigate the SNPs XPC A499V, XPD K751Q XRCC1 R399Q and XRCC3 T241M as potential risk factors and indicators of survival among Caucasian patients. One-hundred-sixty-nine patients as well as 344 healthy controls were included and genotyped with PCR-RFLP. We showed that XPC A499V was associated with increased risk of HNSCC, especially laryngeal carcinoma. Among women, XPD K751Q was associated with increased risk of oral SCC. Furthermore, XPD homozygous mutant individuals had the shortest survival time, a survival time that increased however after full dose radiotherapy. Wild-type individuals of XRCC3 T241M demonstrated an earlier age of onset. HPV-positive never smokers had lower frequencies of p53 mutation. Among HNSCC patients, HPV-positivity was significantly associated with XRCC1 R399Q homozygous mutant genotype. Moreover, combinations of putative risk alleles seemed to act synergistically, increasing the risk of HNSCC. In conclusion, our results suggest that SNPs of the DNA repair genes XPC, XPD, XRCC1, and XRCC3 may affect risk and survival of HNSCC. (C) 2015 Elsevier B.V. All rights reserved.
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- Jamroskovic, Jan, et al.
(author)
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Identification of putative G-quadruplex DNA structures in S. pombe genome by quantitative PCR stop assay
- 2019
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In: DNA Repair. - : Elsevier BV. - 1568-7864 .- 1568-7856. ; 82
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Journal article (peer-reviewed)abstract
- In order to understand in which biological processes the four-stranded G-quadruplex (G4) DNA structures play a role, it is important to determine which predicted regions can actually adopt a G4 structure. Here, to identify DNA regions in Schizosaccharomyces pombe that fold into G4 structures, we first optimized a quantitative PCR (qPCR) assay using the G4 stabilizer, PhenDC3. We call this method the qPCR stop assay, and used it to screen for G4 structures in genomic DNA. The presence of G4 stabilizers inhibited DNA amplification in 14/15 unexplored genomic regions in S. pombe that encompassed predicted G4 structures, suggesting that at these sites the stabilized G4 structure formed an obstacle for the DNA polymerase. Furthermore, the formation of G4 structures was confirmed by complementary in vitro assays. In vivo, the S. pombe G4 unwinder Pif1 helicase, Pfh1, was associated with tested G4 sites, suggesting that the G4 structures also formed in vivo. Thus, we propose that the confirmed G4 structures in S. pombe form an obstacle for replication in vivo, and that the qPCR stop assay is a method that can be used to identify G4 structures. Finally, we suggest that the qPCR stop assay can also be used for identifying G4 structures in other organisms, as well as being adapted to screen for novel G4 stabilizers.
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- Lagunas-Rangel, Francisco Alejandro
(author)
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Current role of mammalian sirtuins in DNA repair
- 2019
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In: DNA Repair. - : Elsevier BV. - 1568-7864 .- 1568-7856. ; 80:2508, s. 85-92
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Research review (peer-reviewed)abstract
- Cellular DNA is constantly challenged by damage-inducing factors derived from exogenous or endogenous sources. Thus, to protect against DNA damage, cells have evolved complex and finely regulated mechanisms collectively known as DNA-damage response (DDR). However, DNA repair in eukaryotes does not occur merely in naked DNA but also within a highly organized and compacted chromatin environment, which ultimately participates in regulating DDR pathways. Thus, remodelling of the chromatin surrounding areas containing damaged DNA is required to allow access to the DNA repair machinery, as well as post-translational modifications in many repair factors to recruit and activate them at the damaged site. Notably, proteins such as sirtuins, which are NAD+-dependent deacetylases, have evolved to modulate multiple repair pathways through deacetylation of some repair factors, influencing chromatin accessibility or indirectly modulating cell cycle and preventing oxidative stress. In this way, the purpose of this review is to summarize the recent knowledge that links sirtuins with DNA repair, with a particular emphasis on the molecular mechanisms associated with coordination and regulation of this vital process.
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