Multiple forms of DNA Damage Caused by UVA Photoactivation of DNA 6‐Thioguanine

Brem, Reto; Karran, Peter

doi:10.1111/j.1751-1097.2011.01043.x

Cited by 65 publications

(66 citation statements)

References 55 publications

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“…They are also widely used as cytotoxic agents of clinical relevance [35,40,41] and in photochemotherapeutic applications to treat skin disorders [42], superficial tumors [43,44], and bladder cancer [45]. However, their prolonged use in patients often leads to phototoxic side effects and skin cancer [26,36,43,62]. Hence, understanding their steady-state and time-resolved photochemistry is intrinsically important.…”

Section: Thiobasesmentioning

confidence: 98%

Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Pollum

Martínez‐Fernández

Crespo‐Hernández

2014

Topics in Current Chemistry

111

200

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The steady-state and time-resolved photochemistry of the natural nucleic acid bases and their sulfur- and nitrogen-substituted analogues in solution is reviewed. Emphasis is given to the experimental studies performed over the last 3-5 years that showcase topical areas of scientific inquiry and those that require further scrutiny. Significant progress has been made toward mapping the radiative and nonradiative decay pathways of nucleic acid bases. There is a consensus that ultrafast internal conversion to the ground state is the primary relaxation pathway in the nucleic acid bases, whereas the mechanism of this relaxation and the level of participation of the (1)πσ*, (1) nπ*, and (3)ππ* states are still matters of debate. Although impressive research has been performed in recent years, the microscopic mechanism(s) by which the nucleic acid bases dissipate excess vibrational energy to their environment, and the role of the N-glycosidic group in this and in other nonradiative decay pathways, are still poorly understood. The simple replacement of a single atom in a nucleobase with a sulfur or nitrogen atom severely restricts access to the conical intersections responsible for the intrinsic internal conversion pathways to the ground state in the nucleic acid bases. It also enhances access to ultrafast and efficient inter-system crossing pathways that populate the triplet manifold in yields close to unity. Determining the coupled nuclear and electronic pathways responsible for the significantly different photochemistry in these nucleic acid base analogues serves as a convenient platform to examine the current state of knowledge regarding the photodynamic properties of the DNA and RNA bases from both experimental and computational perspectives. Further investigations should also aid in forecasting the prospective use of sulfur- and nitrogen-substituted base analogues in photochemotherapeutic applications.

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Section: Thiobasesmentioning

confidence: 98%

Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Pollum

Martínez‐Fernández

Crespo‐Hernández

2014

Topics in Current Chemistry

111

200

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“…Purine salvage by HPRT (1) leads to the incorporation of 6-TG into DNA. DNA 6-TG is a substrate for damage (2) by methylation or by ROS generated from 6-TG-mediated depletion of cellular antioxidants. DNA 6-TG oxidation causes DNA replicationblocking lesions, including ICLs (3).…”

Section: Discussionmentioning

confidence: 99%

“…Other contributors include the formation of toxic thiopurine metabolites and oxidation of DNA 6-TG by exogenous chemicals or ultraviolet A (UVA) radiation (for review see ref. 2).…”

Section: Introductionmentioning

confidence: 99%

Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells

Brem

Karran

2012

Cancer Research

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The thiopurines azathioprine and 6-mercaptopurine have been extensively prescribed as immunosuppressant and anticancer agents for several decades. A third member of the thiopurine family, 6-thioguanine (6-TG), has been used less widely. Although known to be partly dependent on DNA mismatch repair (MMR), the cytotoxicity of 6-TG remains incompletely understood. Here, we describe a novel MMR-independent pathway of 6-TG toxicity. Cell killing depended on two properties of 6-TG: its incorporation into DNA and its ability to act as a source of reactive oxygen species (ROS). ROS targeted DNA 6-TG to generate potentially lethal replication-arresting DNA lesions including interstrand cross-links. These triggered processing by the Fanconi anemia and homologous recombination DNA repair pathways. Allopurinol protected against 6-TG toxicity by acting as a ROS scavenger and preventing DNA damage. Together, our findings provide mechanistic evidence to support the proposed use of thiopurines to treat HR-defective tumors and for the coadministration of 6-TG and allopurinol as an immunomodulation strategy in inflammatory disorders. Cancer Res; 72(18); 4787-95. Ó2012 AACR.

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“…An indication for the induction of the deleterious effects triggered by UVA activation of thiopurines was provided indirectly by the observed inhibition of transcription (207) and abrogation of cell-cycle checkpoints (208) in cultured human cells treated with thiopurine and UVA radiation through the generation of DNA damage. This is explained by the metabolization and incorporation of thiopurines into DNA as 6-thio-2¢-deoxyguanosine, an efficient endogenous Type I and Type II photosensitizer absorbing in the UVA range with a maximum at 342 nm (209). The steady-state photophysics and excited-state dynamics of 6-TG in aqueous solutions have been recently investigated (210).…”

Section: Oxidation Reactions Mediated By Photosensitizersmentioning

confidence: 99%

Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions^†

Cadet¹,

Mouret²,

Ravanat³

et al. 2012

Photochem & Photobiology

267

251

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The survey focuses on recent aspects of photochemical reactions to cellular DNA that are implicated through the predominant formation of mostly bipyrimidine photoproducts in deleterious effects of human exposure to sunlight. Recent developments in analytical methods have allowed accurate and quantitative measurements of the main DNA photoproducts in cells and human skin. Highly mutagenic CC and CT bipyrimidine photoproducts, including cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) are generated in low yields with respect to TT and TC photoproducts. Another striking finding deals with the formation of Dewar valence isomers, the third class of bipyrimidine photoproducts that is accounted for by UVA-mediated isomerization of initially UVB generated 6-4PPs. Cyclobutadithymine (T< >T) has been unambiguously shown to be involved in the genotoxicity of UVA radiation. Thus, T< >T is formed in UVA-irradiated cellular DNA according to a direct excitation mechanism with a higher efficiency than oxidatively generated DNA damage that arises mostly through the Type II photosensitization mechanism. C<>C and C< >T are repaired at rates intermediate between those of T< >T and 6-4TT. Evidence has been also provided for the occurrence of photosensitized reactions mediated by exogenous agents that act either in an independent way or through photodynamic effects.

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Multiple forms of DNA Damage Caused by UVA Photoactivation of DNA 6‐Thioguanine

Cited by 65 publications

References 55 publications

Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells

Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions^†

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Multiple forms of DNA Damage Caused by UVA Photoactivation of DNA 6‐Thioguanine

Cited by 65 publications

References 55 publications

Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells

Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions†

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Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions^†