DNA Damage Recognition
This study uses a novel optical platform for viewing single molecules in real-time moving on DNA and will give a dynamic view of how these protein machines assemble on DNA and track down DNA lesions. This project will test the hypothesis that the bacterial and human NER proteins share similar modes of DNA binding and searching mechanisms for damage detection and processing. Completion of these aims will help to revolutionize the field of DNA repair by developing new imaging techniques that allow direct visualization and real-time measurements of protein complexes in all stages of repair.
They will also begin to address how damage is detected in the context of chromatin. In future years, they will also lay the ground work for imaging single-molecules in real time in living cells. Alterations in NER can cause increased mutations, cancer and cell death and manifest in several human disorders including xeroderma pigmentosum, aging and neurodegeneration. This project will gain insight into how these repair proteins detect and remove DNA damage.
Orphanet: XPA DNA damage recognition and repair factor
Toggle navigation. This extract was created in the absence of an abstract. Excerpt Frequently occurring DNA lesions are continuously removed from mammalian genomes by repair mechanismsthat excise and replace damaged bases and nucleotides.
This Article doi: Article Category Nucleotide Excision Repair. Services Alert me when this article is cited Alert me if a correction is posted Similar articles in this series Similar articles in Web of Science Similar articles in PubMed Download to citation manager. Search for related content.
Latest Complete Volume , Interviews with Speakers - Video. The human skin is increasingly subjected to UV damage due to growing leisure times, the popularity of outdoor activities, frequent traveling to tropical areas and the use of artificial irradiation devices. Concomitantly, the DNA of the skin or mucous membranes is constantly attacked by exogenous or endogenous genotoxins. If not promptly excised by DNA repair machines, the resulting base lesions give rise to mutations, which in turn may cause cancer.
However, DNA repair systems targeting such mutagenic lesions are prone to modulation by skin- or mucous membrane-penetrating xenobiotics. This is the first study that shows a direct effect of low-dose formaldehyde on the assembly of NER complexes. A previous report already suggested that formaldehyde delays DNA repair of UV lesions  but this earlier study was based on indirect measurements whereby transiently appearing single-stranded DNA breaks were taken as circumstantial evidence for ongoing excision repair. One possible scenario to explain our findings is that formaldehyde-induced DPXs are themselves NER substrates that compete with UV lesions for being repaired.
The processing of DPXs is not completely understood but recent studies concluded that the NER pathway plays only a marginal role in the removal of DPXs induced by low-dose formaldehyde . It is believed that site-specific DNA-binding proteins, including DNA repair factors, locate their targets among the vast excess of non-target DNA by facilitated diffusion.https://aneskalori.tk
DNA Damage Recognition Antibodies
In either case, the presence of covalently trapped histones or other chromatin proteins along the DNA path may interrupt such an effective search mode by facilitated diffusion, thereby restricting the rate by which DNA lesions are detected and channeled into DNA repair. That this reduced damage recognition efficiency translates to slower repair has been confirmed by two different tests.
Mechanistically, we found that the observed sequestration of UV-DDB in formaldehyde-damaged chromatin results from transient, non-covalent interactions that delay its movements during the search for DNA damage. Through protein-protein associations, UV-DDB bound to formaldehyde-damaged chromatin also impedes the function of the XPC complex, such that not only the excision of UV lesions but also the repair of chemically induced DNA adducts is diminished.
We also found that the mobility of a representative DNA glycosylase is perturbed by low-dose formaldehyde and that the ensuing BER pathway is inhibited. Further dynamic chromatin transactions may be disturbed by a similar mechanism.
For example, Rager et al. In conclusion, the compromised DNA repair efficiency, reported in this study, raises the possibility that frequent exposures of the skin or mucous membranes to formaldehyde represents an unexpected additional risk factor for cutaneous cancer in combination with UV radiation or chemical carcinogens.
In a broader perspective, the inhibition of DNA excision repair activity by formaldehyde implies that the carcinogenic endpoints of this highly reactive aldehyde may result, to a great extent, from the accumulation of DNA adducts and other mutagenic base lesions induced by constitutively occurring environmental carcinogens or endogenous genotoxic metabolites. In view of this adjuvant effect, we expect that a reduction of formaldehyde exposure in the general population would substantially reduce the overall cancer incidence.
Conceived and designed the experiments: AL HN. Wrote the paper: AL HN. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Objective Formaldehyde is still widely employed as a universal crosslinking agent, preservative and disinfectant, despite its proven carcinogenicity in occupationally exposed workers. Introduction In aging populations, the incidence of chemoresistant malignancies continues to rise.
Cell culture All culture media and supplements were from Invitrogen. Download: PPT. Figure 1. Analysis of repair protein dynamics in living cells. Statistical procedures All results were analyzed with Prism 5 GraphPad Software using the Student's t -test for comparisons. Non-covalent binding to formaldehyde-damaged chromatin The FRAP experiments revealed that UV-DDB remains attached to formaldehyde-damaged chromatin, such that its nuclear movement is inhibited. Figure 4. Indirect formaldehyde-induced reduction of XPC mobility.
Figure 5. Accumulation of damage recognition factors on UV lesions. Differential effects on BER enzymes Another permanent trigger of mutagenesis are oxidative base lesions such as 8-oxo-dG  — . Figure 6. Formaldehyde-induced damage delays the nuclear trafficking of a DNA glycosylase.
Figure 7. Discussion The human skin is increasingly subjected to UV damage due to growing leisure times, the popularity of outdoor activities, frequent traveling to tropical areas and the use of artificial irradiation devices. Acknowledgments We thank Dr.
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