No. 88

April 2013

Headline News Innovation and Development

Applied Technology

Basic Science

Cooperation between CAS and Local Authorities

Bioscience International Cooperation Brief News Geoscience Exchanges with Taiwan, Hong Kong and Macau

Basic Science

Progress Made on DNA Photodamage Reaction Dynamics

Interests in DNA photochemical reaction dynamics have intensified in recent years with the development of powerful spectroscopic and computational techniques, boosting a challenging and promising subfield of molecular reaction dynamics interdisciplinary with molecular biology. In this context, the researchers in the Institute of Chemistry has been devoted in developing the transient IR spectroscopic method to investigate the excited state and free radical reaction dynamics involved in the DNA photodamage, and have made progress in discovering new reaction mechanisms, and thus provided important chemical insights to understand the DNA photodamage at the molecular and quantum state specific levels. Intrinsically, DNA photodamage is caused by the photochemical reactions after the chromophore nucleobases absorb ultraviolet light. The reaction processes may invoke the participation of multiple electronic states (1▲▲*, 1n▲* and 3▲▲*) and significant nonadiabatic effects. For the most abundant lesion, the formation of cyclobutane pyrimidine dimers (CPDs) between adjacent pyrimidine bases by a [2+2] photocycloaddition reaction, the photoproduct formation dynamics of CPD has been detected, from which direct and unequivocal information was acquired about the long-lived triplet state intermediacy possibly involved in DNA photochemistry. The T1/S0 surface intersections were revealed to play significant roles in lowering the reaction barriers and facilitating the photoproduct formation via triplet mechanism (J. Phys. Chem. A. 2011, 115,5335-5345). For another DNA photolesion forming spore photoprocut (SP), which is the cross-link of the methyl group of one thymidine with the C=C double bond of the adjacent thymidine, the consecutive mechanism have been established and shown to follow a nonadiabatic pathway involving both the T1 and S0 states, providing rationale to clarify the long-time debate about the SP formation mechanism. (J. Phys. Chem. B. 2012, 116,11117-11123). The UVA-photocarcinogenesis has been mostly related to oxidative stress caused by Reactive Oxygen Species (ROS). As an end metabolism product of the widely used thiopurine drugs, 6-TG absorbs UVA and produces 1O2 by photosensitization. This unusual photochemical property triggers a variety of DNA damage, among which the oxidation of 6-TG itself by 1O2 to the promutagenic product GSO3 represents one of the major forms. It has been suspected that there exists an initial intermediate, GSO, prior to its further oxidation to GSO2 and GSO3, but GSO has never been observed. Using density functional theory combined with experimental measurements of reaction rate constant and stoichiometry, the elementary reaction pathways and key reaction intermediates have been elucidated, from which a new mechanism via GSOOH?GSO2?GSO4?GSO3 has been discovered and established, solving the mystery of the absence of suspected intermediate GSO in previous experimental detections. The biological aqueous environment was found to play key role in the reaction. From mechanistic and kinetics point of view, these findings provide new chemical insights to understand the high phototoxicity of 6-TG in DNA, and point to methods of using 6-TG as a sensitive fluorescence probe for the quantitative detection of 1O2, which holds particular promise for detecting 1O2 in DNA-related biological surroundings (J. Am. Chem. Soc. 2013, 135,4509-4515).

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