Structural Determinants of Photoreactivity of Triplex Forming Oligonucleotides Conjugated to Psoralens
Triplex-forming oligonucleotides (TFOs) with both DNA and 2′-O-methyl RNA backbones can direct psoralen photoadducts to specific DNA sequences. However, the functional consequences of these differing structures on psoralen photoreactivity are unknown. We designed TFO sequences with DNA and 2′-O-meth...
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Wiley
2010-01-01
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| Series: | Journal of Nucleic Acids |
| Online Access: | http://dx.doi.org/10.4061/2010/523498 |
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| author | Rajagopal Krishnan Dennis H. Oh |
| author_facet | Rajagopal Krishnan Dennis H. Oh |
| author_sort | Rajagopal Krishnan |
| collection | DOAJ |
| description | Triplex-forming oligonucleotides (TFOs) with both DNA and 2′-O-methyl RNA backbones can direct psoralen photoadducts to specific DNA sequences. However, the functional consequences of these differing structures on psoralen photoreactivity are unknown. We designed TFO sequences with DNA and 2′-O-methyl RNA backbones conjugated to psoralen by 2-carbon linkers and examined their ability to bind and target damage to model DNA duplexes corresponding to sequences within the human HPRT gene. While TFO binding affinity was not dramatically affected by the type of backbone, psoralen photoreactivity was completely abrogated by the 2′-O-methyl RNA backbone. Photoreactivity was restored when the psoralen was conjugated to the RNA TFO via a 6-carbon linker. In contrast to the B-form DNA of triplexes formed by DNA TFOs, the CD spectra of triplexes formed with 2′-O-methyl RNA TFOs exhibited features of A-form DNA. These results indicate that 2′-O-methyl RNA TFOs induce a partial B-to-A transition in their target DNA sequences which may impair the photoreactivity of a conjugated psoralen and suggest that optimal design of TFOs to target DNA damage may require a balance between binding ability and drug reactivity. |
| format | Article |
| id | doaj-art-f9161db6f7354ceb9286f85225219782 |
| institution | Kabale University |
| issn | 2090-021X |
| language | English |
| publishDate | 2010-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Nucleic Acids |
| spelling | doaj-art-f9161db6f7354ceb9286f852252197822025-02-03T06:06:06ZengWileyJournal of Nucleic Acids2090-021X2010-01-01201010.4061/2010/523498523498Structural Determinants of Photoreactivity of Triplex Forming Oligonucleotides Conjugated to PsoralensRajagopal Krishnan0Dennis H. Oh1Department of Dermatology, University of California at San Francisco, San Francisco, CA 94121 , USADepartment of Dermatology, University of California at San Francisco, San Francisco, CA 94121 , USATriplex-forming oligonucleotides (TFOs) with both DNA and 2′-O-methyl RNA backbones can direct psoralen photoadducts to specific DNA sequences. However, the functional consequences of these differing structures on psoralen photoreactivity are unknown. We designed TFO sequences with DNA and 2′-O-methyl RNA backbones conjugated to psoralen by 2-carbon linkers and examined their ability to bind and target damage to model DNA duplexes corresponding to sequences within the human HPRT gene. While TFO binding affinity was not dramatically affected by the type of backbone, psoralen photoreactivity was completely abrogated by the 2′-O-methyl RNA backbone. Photoreactivity was restored when the psoralen was conjugated to the RNA TFO via a 6-carbon linker. In contrast to the B-form DNA of triplexes formed by DNA TFOs, the CD spectra of triplexes formed with 2′-O-methyl RNA TFOs exhibited features of A-form DNA. These results indicate that 2′-O-methyl RNA TFOs induce a partial B-to-A transition in their target DNA sequences which may impair the photoreactivity of a conjugated psoralen and suggest that optimal design of TFOs to target DNA damage may require a balance between binding ability and drug reactivity.http://dx.doi.org/10.4061/2010/523498 |
| spellingShingle | Rajagopal Krishnan Dennis H. Oh Structural Determinants of Photoreactivity of Triplex Forming Oligonucleotides Conjugated to Psoralens Journal of Nucleic Acids |
| title | Structural Determinants of Photoreactivity of Triplex Forming Oligonucleotides Conjugated to Psoralens |
| title_full | Structural Determinants of Photoreactivity of Triplex Forming Oligonucleotides Conjugated to Psoralens |
| title_fullStr | Structural Determinants of Photoreactivity of Triplex Forming Oligonucleotides Conjugated to Psoralens |
| title_full_unstemmed | Structural Determinants of Photoreactivity of Triplex Forming Oligonucleotides Conjugated to Psoralens |
| title_short | Structural Determinants of Photoreactivity of Triplex Forming Oligonucleotides Conjugated to Psoralens |
| title_sort | structural determinants of photoreactivity of triplex forming oligonucleotides conjugated to psoralens |
| url | http://dx.doi.org/10.4061/2010/523498 |
| work_keys_str_mv | AT rajagopalkrishnan structuraldeterminantsofphotoreactivityoftriplexformingoligonucleotidesconjugatedtopsoralens AT dennishoh structuraldeterminantsofphotoreactivityoftriplexformingoligonucleotidesconjugatedtopsoralens |