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.

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.  

scholarly journals 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

2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Blanca de Unamuno Bustos ◽  
Natalia Chaparro Aguilera ◽  
Inmaculada Azorin Garcia ◽  
Anaid Calle Andrino ◽  
Margarita Llavador Ros ◽  
...  
Keyword(s):  
Dna Repair ◽  
Medical Device ◽  
Actinic Keratosis ◽  
Enzyme Complex ◽  
Repair Enzyme ◽  
Term Efficacy ◽  
Treatment And Prevention ◽  
Cancerization Field

Abstract 239: p53 Protects Cardiac Stem Cells From the Toxic Effects of Chemotherapy and Controls their Fate

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ramaswamy Kannappan ◽  
Giorgia Palano ◽  
Polina Goichberg ◽  
Fumihiro Sanada ◽  
Sergio Signore ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Dna Repair ◽  
Critical Role ◽  
Dna Lesions ◽  
Toxic Effects ◽  
Cardiac Stem Cells ◽  
Inhibition Of Proliferation ◽  
P53 Expression

Doxorubicin (DOXO) causes dilated cardiomyopathy and heart failure. We have documented previously that DOXO-mediated cardiotoxicity is dictated by functional alterations of cardiac stem cells (CSCs). DOXO-induced myopathy was coupled with a reduction in CSC number due to increased death, inhibition of proliferation, and senescence. We raised the possibility that survival and growth of CSCs following DOXO treatment may be enhanced by modulating the intracellular level of p53, which plays a critical role in the determination of stem cell fate. For this purpose, transgenic mice carrying an additional p53 allele (Sp53) were studied. With respect to wild-type mice (WT), CSCs isolated from Sp53 mice (Sp53-CSCs) showed increased apoptosis with accumulation of the pro-apoptotic p53 targets BAX, PUMA and Pidd. Conversely, the expression of p21Cip1, a cell cycle inhibitor and inducer of cell senescence, was lower in Sp53-CSCs than WT cells. Upon DOXO treatment, Sp53-CSCs exhibited accelerated onset of apoptosis. However, viable Sp53-CSCs showed enhanced formation of DNA damage response foci, indicative of a very efficient DNA repair mechanism. Following removal of DOXO, Sp53-CSCs re-entered the cell cycle and divided, while WT cells continued to die by apoptosis or became senescent. The response of WT-CSCs to DOXO involved the pro-apoptotic Bcl2 family member Noxa and the senescence-associated protein p16INK4a. In contrast, exposure of Sp53-CSCs to DOXO provoked pulses of p53 expression, which favored sustained upregulation of Mdm2. Mdm2 antagonized the inhibitory effect of p53 on cell growth and prevented apoptosis. Ultimately, Sp53-CSCs showed accumulation of PCNA, which is required for DNA repair and synthesis. Importantly, IGF-1 release was higher in Sp53-CSCs, promoting their replication through an autocrine-paracrine mechanism. Collectively, our data demonstrate that changes in the pattern of p53 expression have beneficial effects on CSCs by amplifying the DNA repair response, facilitating the clearance of cells with non-repairable DNA damage, and enabling the proliferation of cells in which DNA lesions are effectively removed. Thus, targeting p53 expression in CSCs may protect the heart from the toxic effects of chemotherapy.

scholarly journals Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2073
Author(s):  
Beate Köberle ◽  
Sarah Schoch
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Platinum Complexes ◽  
Dna Lesions ◽  
Dna Damage Signaling ◽  
Repair Mechanisms ◽  
P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

scholarly journals The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 479
Author(s):  
Pavel Vodicka ◽  
Ladislav Andera ◽  
Alena Opattova ◽  
Ludmila Vodickova
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Lesions ◽  
Cell Cycle Checkpoint ◽  
Solid Cancer ◽  
Genomic Integrity ◽  
Repair Capacity ◽  
Mutational Status ◽  
Telomere Homeostasis

The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.

scholarly journals TAT-Mediated Delivery of a DNA Repair Enzyme to Skin Cells Rapidly Initiates Repair of UV-Induced DNA Damage

2011 ◽  
Vol 131 (3) ◽  
pp. 753-761 ◽  
Author(s):  
Jodi L. Johnson ◽  
Brian C. Lowell ◽  
Olga P. Ryabinina ◽  
R. Stephen Lloyd ◽  
Amanda K. McCullough
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Repair Enzyme ◽  
Skin Cells

scholarly journals Large-scale heterochromatin remodeling linked to overreplication-associated DNA damage

2016 ◽  
Vol 114 (2) ◽  
pp. 406-411 ◽  
Author(s):  
Wei Feng ◽  
Christopher J. Hale ◽  
Ryan S. Over ◽  
Shawn J. Cokus ◽  
Steven E. Jacobsen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Large Scale ◽  
Double Strand Breaks ◽  
Repair Enzyme ◽  
Strand Breaks ◽  
Histone 3 ◽  
Challenging Environment ◽  
Chromatin Density ◽  
Being Moved

Previously, we have shown that loss of the histone 3 lysine 27 (H3K27) monomethyltransferases ARABIDOPSIS TRITHORAX-RELATED 5 (ATXR5) and ATXR6 (ATXR6) results in the overreplication of heterochromatin. Here we show that the overreplication results in DNA damage and extensive chromocenter remodeling into unique structures we have named “overreplication-associated centers” (RACs). RACs have a highly ordered structure with an outer layer of condensed heterochromatin, an inner layer enriched in the histone variant H2AX, and a low-density core containing foci of phosphorylated H2AX (a marker of double-strand breaks) and the DNA-repair enzyme RAD51. atxr5,6 mutants are strongly affected by mutations in DNA repair, such as ATM and ATR. Because of its dense packaging and repetitive DNA sequence, heterochromatin is a challenging environment in which to repair DNA damage. Previous work in animals has shown that heterochromatic breaks are translocated out of the heterochromatic domain for repair. Our results show that atxr5,6 mutants use a variation on this strategy for repairing heterochromatic DNA damage. Rather than being moved to adjacent euchromatic regions, as in animals, heterochromatin undergoes large-scale remodeling to create a compartment with low chromatin density.

scholarly journals Mutational signatures are jointly shaped by DNA damage and repair

2019 ◽  
Author(s):  
Nadezda V Volkova ◽  
Bettina Meier ◽  
Víctor González-Huici ◽  
Simone Bertolini ◽  
Santiago Gonzalez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Dna Lesions ◽  
Single Nucleotide Variants ◽  
Mutational Signatures ◽  
Experimental Conditions ◽  
Repair Deficiency ◽  
Dna Repair Deficiency ◽  
Mutation Spectra

AbstractMutations arise when DNA lesions escape DNA repair. To delineate the contributions of DNA damage and DNA repair deficiency to mutagenesis we sequenced 2,717 genomes of wild-type and 53 DNA repair defective C. elegans strains propagated through several generations or exposed to 11 genotoxins at multiple doses. Combining genotoxin exposure and DNA repair deficiency alters mutation rates or leads to unexpected mutation spectra in nearly 40% of all experimental conditions involving 9/11 of genotoxins tested and 32/53 genotypes. For 8/11 genotoxins, signatures change in response to more than one DNA repair deficiency, indicating that multiple genes and pathways are involved in repairing DNA lesions induced by one genotoxin. For many genotoxins, the majority of observed single nucleotide variants results from error-prone translesion synthesis, rather than primary mutagenicity of altered nucleotides. Nucleotide excision repair mends the vast majority of genotoxic lesions, preventing up to 99% of mutations. Analogous mutagenic DNA damage-repair interactions can also be found in cancers, but, except for rare cases, effects are weak owing to the unknown histories of genotoxic exposures and DNA repair status. Overall, our data underscore that mutation spectra are joint products of DNA damage and DNA repair and imply that mutational signatures computationally derived from cancer genomes are more variable than currently anticipated.

scholarly journals Recent advances in the nucleolar responses to DNA double-strand breaks

2020 ◽  
Vol 48 (17) ◽  
pp. 9449-9461
Author(s):  
Lea Milling Korsholm ◽  
Zita Gál ◽  
Blanca Nieto ◽  
Oliver Quevedo ◽  
Stavroula Boukoura ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Ribosomal Dna ◽  
Repetitive Sequences ◽  
Dna Lesions ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Damage Response

Abstract DNA damage poses a serious threat to human health and cells therefore continuously monitor and repair DNA lesions across the genome. Ribosomal DNA is a genomic domain that represents a particular challenge due to repetitive sequences, high transcriptional activity and its localization in the nucleolus, where the accessibility of DNA repair factors is limited. Recent discoveries have significantly extended our understanding of how cells respond to DNA double-strand breaks (DSBs) in the nucleolus, and new kinases and multiple down-stream targets have been identified. Restructuring of the nucleolus can occur as a consequence of DSBs and new data point to an active regulation of this process, challenging previous views. Furthermore, new insights into coordination of cell cycle phases and ribosomal DNA repair argue against existing concepts. In addition, the importance of nucleolar-DNA damage response (n-DDR) mechanisms for maintenance of genome stability and the potential of such factors as anti-cancer targets is becoming apparent. This review will provide a detailed discussion of recent findings and their implications for our understanding of the n-DDR. The n-DDR shares features with the DNA damage response (DDR) elsewhere in the genome but is also emerging as an independent response unique to ribosomal DNA and the nucleolus.

scholarly journals The Dark Side of UV-Induced DNA Lesion Repair

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1450
Author(s):  
Wojciech Strzałka ◽  
Piotr Zgłobicki ◽  
Ewa Kowalska ◽  
Aneta Bażant ◽  
Dariusz Dziga ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Uv Light ◽  
Genetic Material ◽  
Dna Lesions ◽  
Dark Side ◽  
Repair System ◽  
Strand Breaks ◽  
Dna Lesion ◽  
Pyrimidine Dimers

In their life cycle, plants are exposed to various unfavorable environmental factors including ultraviolet (UV) radiation emitted by the Sun. UV-A and UV-B, which are partially absorbed by the ozone layer, reach the surface of the Earth causing harmful effects among the others on plant genetic material. The energy of UV light is sufficient to induce mutations in DNA. Some examples of DNA damage induced by UV are pyrimidine dimers, oxidized nucleotides as well as single and double-strand breaks. When exposed to light, plants can repair major UV-induced DNA lesions, i.e., pyrimidine dimers using photoreactivation. However, this highly efficient light-dependent DNA repair system is ineffective in dim light or at night. Moreover, it is helpless when it comes to the repair of DNA lesions other than pyrimidine dimers. In this review, we have focused on how plants cope with deleterious DNA damage that cannot be repaired by photoreactivation. The current understanding of light-independent mechanisms, classified as dark DNA repair, indispensable for the maintenance of plant genetic material integrity has been presented.

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