Mutagenic Consequences Of Chemical Reaction with DNA
Philip L. Grover in Chemical Carcinogens and DNA, 2019
It is not possible to consider chemical mutagenesis separately from DNA repair, because of the dual importance of repair in removing potentially mutagenic lesions from the DNA, and in converting such lesions into mutations. As a starting point, the author will try to describe our current knowledge of how DNA damage is accurately repaired by E. coli. Primarily, ultraviolet light (UV) induced damage will be discussed, and the responses of the bacterium to the whole spectrum of chemical carcinogens can then be considered as variations on a basic theme. UV is by far the most comprehensively investigated DNA damaging agent, and E. coli its most studied victim. As a reference agent, UV has several advantages, including easy administration, accurate dosimetry, and virtually instant treatment for kinetic studies. Moreover, the principal lesion is well characterized. Pyrimidine dimers are formed in which adjacent pyrimi-dines on the same DNA strand are joined by a cyclobutane type ring.38 Formation of the cyclobutane structure saturates the 5,6-double bond in the pyrimidine ring, causing it to become nonplanar.
The Chronic Effects of Ultraviolet Radiation on the Skin: Photoaging
Henry W. Lim, Herbert Hönigsmann, John L. M. Hawk in Photodermatology, 2007
It is well documented that many DNA damaging agents also produce aging-like changes. Such agents include UV irradiation, ROS, cigarette smoke (presumably the carcinogen benzo(a)pyrene), and many chemotherapeutic drugs, notably cisplatin (36). UV irradiation causes pyrimidine dimers, most commonly between adjacent thymidines (37), ROS primarily cause 8-oxo-guanine, and the other agents form adducts that alter DNA at guanine nucleotides (38,39). In this context, it is interesting that one-third of the TTAGGG telomere overhang repeat sequence is dithymidines (TT) and half is guanine (G) residues (35). The resultant concentration of UVor chemical carcinogen damage in the telomere might therefore reasonably lead to disruption of the loop structure and exposure of the overhang, followed by DNA damage signaling. Certainly, signaling through the p53 pathway is well documented after exposure to UV (40) or other DNA-damaging agents (41), as well as during entry into senescence [for review, see (42)].
Basic Principles in Photomedicine and Photochemistry
Henry W. Lim, Nicholas A. Soter in Clinical Photomedicine, 2018
Photoaddition reactions usually involve interaction of an excited state molecule with a ground state molecule. In the photoproduct, the two molecules are covalently linked. The excited state molecule may react with a ground state molecule of the same type. For example, dimers are formed between adjacent thymines on a strand of DNA when one of the thymines is photoactivated (Eq. 4). These photoproducts have been measured in human skin exposed to UV radiation. UVB radiation is most effective but dimers were detected after exposure of skin to wavelengths as long as 375 nm (1). Cyclobutyl pyrimidine dimers and another type of dimer involving the carbon-nitrogen exocyclic double bond of cytosine (called the 6–4 photoproduct) are believed to be the major products responsible for mutagenic and toxic effects of UV radiation (2).
Differential expression of flowering genes in Arabidopsis thaliana under chronic and acute ionizing radiation
Published in International Journal of Radiation Biology, 2019
Maryna V. Kryvokhyzha, Konstantin V. Krutovsky, Namik M. Rashydov
Early flowering of A. thaliana in response to drought stress, UV-C, and pathogens (for example, Fusarium oxysporum infection) was demonstrated recently (Takeno 2016). We observed that the low dose of 3 cGy irradiation exposure also promotes early flowering in A. thaliana plants. Published studies have also shown that the FT gene could be involved in stress-induced flowering (Takeno 2012). However, we did not observe its increased expression in earlier flowering (King et al. 2008). The photoperiodic CO gene was upregulated and followed by flowering acceleration. Our study has shown that the effects of the 17 cGy chronic and 15 Gy acute irradiations were similar to the UV-B effect (Ali et al. 2015). The short-wavelength UV light can cause photolesions and cyclobutane–pyrimidine dimers in DNA and its structural disintegration (Brem et al. 2017; Chen et al. 2017).
Prospects of topical protection from ultraviolet radiation exposure: a critical review on the juxtaposition of the benefits and risks involved with the use of chemoprotective agents
Published in Journal of Dermatological Treatment, 2018
Nilutpal Sharma Bora, Bhaskar Mazumder, Pronobesh Chattopadhyay
Pyrimidine dimers are the most representative DNA lesion, which represents the genotoxic effects of the UVB radiation and are mainly mediated by the direct absorption of photons by DNA (38). Exogenous molecules (eg, photosensitizing drugs) also get activated by sunlight, which can increase the risk of photocarcinogenesis. Some of these molecules react directly with DNA (eg, psoralens), whereas others cause damage by generating a local oxidative stress (eg, antibiotics and nonsteroidal anti-inflammatory drug) (39). Photosensitization of DNA by chemicals can also increase the risk of photocarcinogenesis; for example, psoralen plus UVA therapy or antibiotic treatment such as fluoroquinolones (38).
Novel insights into the pathogenesis and treatment of NRAS mutant melanoma
Published in Expert Review of Precision Medicine and Drug Development, 2021
Jeffrey Zhao, Carlos Galvez, Kathryn Eby Beckermann, Douglas B. Johnson, Jeffrey A Sosman
Though canonical driver [44] mutations in NRAS are causally related to tumor formation in model systems, the development of human cutaneous melanoma from normal skin and precursor lesions is multifactorial. Human melanomas featuring these mutations arise in a complex series of steps at the intersection of environmental risk factors including UV exposure as well as germline genetic variants. Sun exposure (from chronic intermittent environmental sources) has been shown to be the major environmental risk factor for WHO pathway I–III melanomas (including superficial spreading, lentigo maligna, desmoplastic histologic subtypes) and nodular melanomas [45]. The role of UV radiation in NRAS-mutant melanoma pathogenesis is complex, as sun damage does not appear to be a requirement for the development of genetic alterations at the NRAS locus as demonstrated by the presence of these mutations in acral and mucosal subtypes as well as melanomas arising in a congenital nevus (WHO V, VI, and VII). Non-sun exposed melanomas – including acral lentiginous melanomas – also harbor NRAS mutations but less frequently than sun-associated melanomas [46]. For UV-associated melanomas, irradiation appears to mediate base pair mutagenesis in-vitro and in-vivo within the confines of the NRAS gene. UV exposure produces signature cyclobutane pyrimidine dimers at codons 12, 13, and 61. Compared to the heterogeneity of UV signature mutations seen at other loci including TP53, CDKN2A (p16INK4A) and PTEN/MMAC1, UV-associated lesions that fall within NRAS are positioned in a highly stereotypical manner at just a few genomic hot spots [1]. Interactions between UV exposure and tumor genetic background appear to be codon-specific, with transgenic NRASQ61R but not NRASG12D mice developing increased rates of tumor formation after UV treatment [47].
Related Knowledge Centers
- Cytosine
- Dimerization
- DNA
- Nucleotide
- Pyrimidine
- Rna
- Thymine
- Ultraviolet
- Molecular Lesion
- Organic Photochemistry