Mechanistic Investigation of Photo-Induced DNA Interstrand Cross-Link (ICL) Formation by Substituted Benzene Analogues
Mentor 1
Xiaohua Peng
Mentor 2
Nurul Islam Setu
Start Date
16-4-2021 12:00 AM
Description
For cell division, DNA transcription and replication are vital biological processes that require the temporary separation of two strands of duplex DNA. DNA interstrand cross-link (ICL) covalently links two DNA strands preventing them from dissociation which in turn inhibits cell division. Thus, DNA ICL agents are widely used as anticancer agents. In addition, they are also used for DNA damage and repair study, nucleic acid detection and construction of DNA nanomaterials. The objective of this study is to perform a mechanistic investigation of DNA interstrand cross-linking by modified nucleoside upon X-ray or UV irradiation. We have designed several modified nucleosides with modified base moieties as well as bifunctional aromatic rings capable of cross-linking DNA upon photoirradiation. After the synthesis of the modified nucleosides, they will be incorporated into DNA strands by solid-phase DNA synthesis. The photo reactivities of these molecules towards DNA will be investigated by DNA cross-linking assay upon UV- or X-ray irradiation. The mechanism of DNA ICL formation or DNA strand cleavage will be investigated by using different techniques, including radical and carbocation trapping, PAGE analysis of ICL efficiency, NMR and mass analysis of DNA ICL product, etc. The study will help to understand the cross-linking pattern by the modified nucleosides which can assist to optimize the structure of ICL agents with superior biological activity and also focus on ICL damage with its feedback and connection to cancer development and its treatment.
Mechanistic Investigation of Photo-Induced DNA Interstrand Cross-Link (ICL) Formation by Substituted Benzene Analogues
For cell division, DNA transcription and replication are vital biological processes that require the temporary separation of two strands of duplex DNA. DNA interstrand cross-link (ICL) covalently links two DNA strands preventing them from dissociation which in turn inhibits cell division. Thus, DNA ICL agents are widely used as anticancer agents. In addition, they are also used for DNA damage and repair study, nucleic acid detection and construction of DNA nanomaterials. The objective of this study is to perform a mechanistic investigation of DNA interstrand cross-linking by modified nucleoside upon X-ray or UV irradiation. We have designed several modified nucleosides with modified base moieties as well as bifunctional aromatic rings capable of cross-linking DNA upon photoirradiation. After the synthesis of the modified nucleosides, they will be incorporated into DNA strands by solid-phase DNA synthesis. The photo reactivities of these molecules towards DNA will be investigated by DNA cross-linking assay upon UV- or X-ray irradiation. The mechanism of DNA ICL formation or DNA strand cleavage will be investigated by using different techniques, including radical and carbocation trapping, PAGE analysis of ICL efficiency, NMR and mass analysis of DNA ICL product, etc. The study will help to understand the cross-linking pattern by the modified nucleosides which can assist to optimize the structure of ICL agents with superior biological activity and also focus on ICL damage with its feedback and connection to cancer development and its treatment.
