Both DNA global deformation and repair enzyme contacts mediate flipping of thymine dimer damage

AbstractMolecular dynamics (MD) studies of several radiation originated lesions on the DNA molecules are presented. The pyrimidine lesions (cytosinyl radical, thymine dimer, thymine glycol) and purine lesion (8-oxoguanine) were subjected to the MD simulations for several hundred picoseconds using MD simulation code AMBER 5.0 (4.0). The simulations were performed for fully dissolved solute molecules in water. Significant structural changes in the DNA double helical structure were observed in all cases which may be categorized as: a) the breaking of hydrogen bonds network between complementary bases and resulted opening of the double helix (cytosinyl, radical, 8-oxoguanine); b) the sharp bending of the DNA helix centered at the lesion site (thymine dimer, thymine glycol); and c) the flippingout of adenine on the strand complementary to the lesion (8-oxoguanine). These changes related to the overall collapsing of the double helical structure around the lesion, are expected to facilitate the docking of the repair enzyme into the DNA in the formation of DNA-enzyme complex. The stable DNA-enzyme complex is a necessary condition for the onset of the enzymatic repair process. In addition to structural changes, specific values of electrostatic interaction energy were determined at several lesion sites (thymine dimer, thymine glycol and 8-oxoguanine). This lesion-specific electrostatic energy is a factor that enables repair enzyme to discriminate lesion from the native site during the scanning of the DNA surface.

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DNA Repair Enzyme Topical Agent

10.32388/618e5i ◽

2020 ◽

Author(s):

Keyword(s):

Dna Repair ◽

Topical Agent ◽

Repair Enzyme

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Long-term efficacy of a new medical device containing Fernblock® and DNA repair enzyme complex in the treatment and prevention of cancerization field in patients with actinic keratosis.

Journal of Current Medical Research and Opinion ◽

10.15520/jcmro.v2i02.129 ◽

2019 ◽

Vol 2 (02) ◽

pp. 80-89

Author(s):

Blanca De Unamuno Bustos ◽

Natalia Chaparr´´o Aguilera ◽

Inmaculada Azorín García ◽

Anaid Calle Andrino ◽

Margarita Llavador Ros ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Medical Device ◽

Actinic Keratosis ◽

Statistical Significance ◽

Dna Lesions ◽

Enzyme Complex ◽

Repair Enzyme ◽

P53 Expression ◽

Cancerization Field

Actinic keratosis (AKs) are part of the cancerization field, a region adjacent to AKs containing subclinical and histologically abnormal epidermal tissue due to Ultraviolet (UV)-induced DNA damage. The photoproducts as consequence of DNA damage induced by UV are mainly cyclobutane pyrimidine dimers (CPDs). Fernblock® demonstrated in previous studies significant reduction of the number of CPDs induced by UV radiation. Photolyases are a specific group of enzymes that remove the major UV-induced DNA lesions by a mechanism called photo-reactivation. A monocentric, prospective, controlled, and double blind interventional study was performed to evaluate the effect of a new medical device (NMD) containing a DNA-repair enzyme complex (photolyases, endonucleases and glycosilases), a combination of UV-filters, and Fernblock® in the treatment of the cancerization field in 30 AK patients after photodynamic therapy. Patients were randomized into two groups: patients receiving a standard sunscreen (SS) andpatients receiving the NMD. Clinical, dermoscopic, reflectance confocal microscopy (RCM) and histological evaluations were performed. An increase of AKs was noted in all groups after three months of PDT without significant differences between them (p=0.476). A significant increase in the number of AKs was observed in SS group after six (p=0.026) and twelve months of PDT (p=0.038); however, this increase did not reach statistical significance in the NMD group. Regarding RCM evaluation, honeycomb pattern assessment after twelve months of PDT showed significant differences in the extension and grade of the atypia in the NMD group compared to SS group (p=0.030 and p=0.026, respectively). Concerning histopathological evaluation, keratinocyte atypia grade improved from baseline to six months after PDT in all the groups, with no statistically significant differences between the groups. Twelve months after PDT, p53 expression was significantly lower in the NMD group compared to SS group (p=0.028). The product was well-tolerated, with no serious adverse events reported. Our results provide evidence of the utility of this NMD in the improvement of the cancerization field and in the prevention of the development of new AKs.

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Faculty Opinions recommendation of DNA polymerase lambda, a novel DNA repair enzyme in human cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005644.66906 ◽

2002 ◽

Author(s):

Errol C Friedberg

Keyword(s):

Dna Repair ◽

Dna Polymerase ◽

Human Cells ◽

Repair Enzyme

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The Development of Tyrosyl-DNA Phosphodyesterase 1 (TDP1) Inhibitors Based on the Amines Combining Aromatic/Heteroaromatic and Monoterpenoid Moieties

Letters in Drug Design & Discovery ◽

10.2174/1570180816666181220121042 ◽

2019 ◽

Vol 16 (5) ◽

pp. 597-605 ◽

Cited By ~ 1

Author(s):

Evgenii Mozhaitsev ◽

Evgenii Suslov ◽

Yuliya Demidova ◽

Dina Korchagina ◽

Konstantin Volcho ◽

...

Keyword(s):

Dna Repair ◽

Tumor Cell ◽

13C Nmr ◽

Inhibitory Activity ◽

Secondary Amines ◽

Repair Enzyme ◽

1H And 13C Nmr ◽

Chemical Structures ◽

Natural Substances ◽

Micromolar Range

Background: Inhibition of the DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), may increase the efficacy of cancer drugs that cause damage to tumor cell DNA. Among the known TDP1 inhibitors, there are compounds containing moieties of natural substances, e.g., monoterpenoids. In this work, we synthesized several compounds containing aromatic/ heteroaromatic amines and monoterpenoid groups and assessed their TDP1 inhibition potential. Methods: Structures of all the synthesized compounds were confirmed by 1H and 13C NMR as well as HRMS. The TDP1 inhibitory activity of the amines was determined by real-time fluorescence oligonucleotide biosensor. Results: The synthesized secondary amines had TDP1 inhibitory activity IC50 in the range of 0.79-9.2 µM. The highest activity was found for (–)-myrtenal derivatives containing p-bromoaniline or m-(trifluoromethyl)aniline residue. Conclusion: We synthesized 22 secondary amines; of these, 17 amines are novel chemical structures. Many of the amines inhibit TDP1 activity in the low micromolar range. Therefore, these compounds are promising for further study of their antiproliferative activity in conjunction with DNA damaging drugs.

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Electrophilic Properties of 2′-Deoxyadenosine···Thymine Dimer: Photoelectron Spectroscopy and DFT Studies

The Journal of Physical Chemistry A ◽

10.1021/acs.jpca.1c03803 ◽

2021 ◽

Author(s):

Piotr Storoniak ◽

Janusz Rak ◽

Haopeng Wang ◽

Yeon Jae Ko ◽

Kit H. Bowen

Keyword(s):

Photoelectron Spectroscopy ◽

Dft Studies ◽

Thymine Dimer

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Visualization of the Strain-Rate State of a Data Cloud: Analysis of the Temporal Change of an Urban Multivariate Description

Applied Sciences ◽

10.3390/app9142920 ◽

2019 ◽

Vol 9 (14) ◽

pp. 2920

Author(s):

Lorena Salazar-Llano ◽

Camilo Bayona-Roa

Keyword(s):

Strain Rate ◽

Temporal Change ◽

Three Dimensional ◽

Urban System ◽

Deformation Pattern ◽

Analysis Methodology ◽

Global Deformation ◽

Temporal Rate ◽

Cloud Of Points ◽

Entire Dataset

One challenging problem is the representation of three-dimensional datasets that vary with time. These datasets can be thought of as a cloud of points that gradually deforms. However, point-wise variations lack information about the overall deformation pattern, and, more importantly, about the extreme deformation locations inside the cloud. This present article applies a technique in computational mechanics to derive the strain-rate state of a time-dependent and three-dimensional data distribution, by which one can characterize its main trends of shift. Indeed, the tensorial analysis methodology is able to determine the global deformation rates in the entire dataset. With the use of this technique, one can characterize the significant fluctuations in a reduced multivariate description of an urban system and identify the possible causes of those changes: calculating the strain-rate state of a PCA-based multivariate description of an urban system, we are able to describe the clustering and divergence patterns between the districts of a city and to characterize the temporal rate in which those variations happen.

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