Sequence and pH Effects of LNA-Containing Triple Helix-Forming Oligonucleotides: Physical Chemistry, Biochemistry, and Modeling Studies
Triple helix-forming oligonucleotides (TFOs) have been demonstrated to be capable of interfering with gene expression and modifying genomic DNA in a sequence-specific manner. Partial incorporation of 2‘-O,4‘-C-methylene linked locked nucleic acid (LNA) residues in TFOs has been shown to enhance sign...
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| Veröffentlicht in: | Biochemistry (Easton) 2004-04, Vol.43 (14), p.4160-4169 |
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| container_title | Biochemistry (Easton) |
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| creator | Sun, Bei-Wen Babu, B. Ravindra Sørensen, Mads D Zakrzewska, Krystyna Wengel, Jesper Sun, Jian-Sheng |
| description | Triple helix-forming oligonucleotides (TFOs) have been demonstrated to be capable of interfering with gene expression and modifying genomic DNA in a sequence-specific manner. Partial incorporation of 2‘-O,4‘-C-methylene linked locked nucleic acid (LNA) residues in TFOs has been shown to enhance significantly triple helix formation, whereas the full-length LNA TFO failed to form a stable triplex. This work is aimed at understanding the triple helix-forming properties of LNA-containing TFOs and at optimally designing their sequences. Both DNA thermal melting, gel retardation, and restriction enzyme experiments as well as modeling studies by molecular mechanics were carried out to investigate the base composition/sequence and pH-dependence effects of LNA-containing TFOs, as well as their structural features underlying triple helix formation. Alternating LNA substitution every 2−3 nucleotides in TFOs is mandatory, whereas the use of thymine LNA residues should be favored under neutral pH conditions. A rule for designing optimal LNA-containing TFOs is proposed. In addition, alternative LNA and 2‘-O-methyl residues in TFOs do not significantly improve triple helix formation. |
| doi_str_mv | 10.1021/bi036064e |
| format | Article |
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Both DNA thermal melting, gel retardation, and restriction enzyme experiments as well as modeling studies by molecular mechanics were carried out to investigate the base composition/sequence and pH-dependence effects of LNA-containing TFOs, as well as their structural features underlying triple helix formation. Alternating LNA substitution every 2−3 nucleotides in TFOs is mandatory, whereas the use of thymine LNA residues should be favored under neutral pH conditions. A rule for designing optimal LNA-containing TFOs is proposed. 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Both DNA thermal melting, gel retardation, and restriction enzyme experiments as well as modeling studies by molecular mechanics were carried out to investigate the base composition/sequence and pH-dependence effects of LNA-containing TFOs, as well as their structural features underlying triple helix formation. Alternating LNA substitution every 2−3 nucleotides in TFOs is mandatory, whereas the use of thymine LNA residues should be favored under neutral pH conditions. A rule for designing optimal LNA-containing TFOs is proposed. In addition, alternative LNA and 2‘-O-methyl residues in TFOs do not significantly improve triple helix formation.</description><subject>Base Sequence</subject><subject>Biochemistry, Molecular Biology</subject><subject>Deoxyribonucleases, Type II Site-Specific - chemistry</subject><subject>DNA - chemistry</subject><subject>Hot Temperature</subject><subject>Hydrocarbons</subject><subject>Hydrogen-Ion Concentration</subject><subject>Hydrolysis</subject><subject>Life Sciences</subject><subject>Methane - analogs & derivatives</subject><subject>Methane - chemistry</subject><subject>Models, Molecular</subject><subject>Nucleic Acid Conformation</subject><subject>Nucleic Acid Heteroduplexes - chemistry</subject><subject>Oligodeoxyribonucleotides - chemistry</subject><subject>Purine Nucleotides - chemistry</subject><subject>Pyrimidine Nucleotides - chemistry</subject><subject>Restriction Mapping</subject><subject>Spectrophotometry, Ultraviolet</subject><subject>Thermodynamics</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEUhS0EomlhwQsgb0CqxMD1zPiPXYhagkhpIWFteTyexmUyDvYManZs4TF5EhwlSjZIrKx7_ekc-xyEnhF4TSAnbyoHBQNW2gdoRGgOWSklfYhGAMCyXDI4Qacx3qWxBF4-RieEAqOCyhH6PbffB9sZi3VX4_UUXzSNNX3EvsGzT-Ns4rteu851t3gR3Lq1eGpbd59d-rDaLq9bd-u7wbTW96628e2fn7_wzXITndEtniztysU-bF7hd86b47Q1u_J1kkoa836onY1P0KNGt9E-3Z9n6OvlxWIyzWbX7z9MxrNMlwL6jNGKMkpoTUVVaKEpiMbIUufQaC4EoQW1JeVgSF03UlYgc0IF48ZC2lpenKHzne5St2od3EqHjfLaqel4prY7gIKUsqQ_SGJf7th18Cmn2Kv0A2PbVnfWD1FxIoBw-n-QcMkkUDi6m-BjDLY5PIGA2rapDm0m9vledKhWtj6S-_oSkO2AFKu9P9zr8E0xXnCqFjdz9XnOrr58pEIViX-x47WJ6s4PoUtB_8P4L-I1tOQ</recordid><startdate>20040413</startdate><enddate>20040413</enddate><creator>Sun, Bei-Wen</creator><creator>Babu, B. 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Ravindra ; Sørensen, Mads D ; Zakrzewska, Krystyna ; Wengel, Jesper ; Sun, Jian-Sheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a480t-65b56515d58b3a8a508fc94a20fa7881535e4570c1ddf99b09215867ce0570e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Base Sequence</topic><topic>Biochemistry, Molecular Biology</topic><topic>Deoxyribonucleases, Type II Site-Specific - chemistry</topic><topic>DNA - chemistry</topic><topic>Hot Temperature</topic><topic>Hydrocarbons</topic><topic>Hydrogen-Ion Concentration</topic><topic>Hydrolysis</topic><topic>Life Sciences</topic><topic>Methane - analogs & derivatives</topic><topic>Methane - chemistry</topic><topic>Models, Molecular</topic><topic>Nucleic Acid Conformation</topic><topic>Nucleic Acid Heteroduplexes - chemistry</topic><topic>Oligodeoxyribonucleotides - chemistry</topic><topic>Purine Nucleotides - chemistry</topic><topic>Pyrimidine Nucleotides - chemistry</topic><topic>Restriction Mapping</topic><topic>Spectrophotometry, Ultraviolet</topic><topic>Thermodynamics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Bei-Wen</creatorcontrib><creatorcontrib>Babu, B. Ravindra</creatorcontrib><creatorcontrib>Sørensen, Mads D</creatorcontrib><creatorcontrib>Zakrzewska, Krystyna</creatorcontrib><creatorcontrib>Wengel, Jesper</creatorcontrib><creatorcontrib>Sun, Jian-Sheng</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Bei-Wen</au><au>Babu, B. 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Partial incorporation of 2‘-O,4‘-C-methylene linked locked nucleic acid (LNA) residues in TFOs has been shown to enhance significantly triple helix formation, whereas the full-length LNA TFO failed to form a stable triplex. This work is aimed at understanding the triple helix-forming properties of LNA-containing TFOs and at optimally designing their sequences. Both DNA thermal melting, gel retardation, and restriction enzyme experiments as well as modeling studies by molecular mechanics were carried out to investigate the base composition/sequence and pH-dependence effects of LNA-containing TFOs, as well as their structural features underlying triple helix formation. Alternating LNA substitution every 2−3 nucleotides in TFOs is mandatory, whereas the use of thymine LNA residues should be favored under neutral pH conditions. A rule for designing optimal LNA-containing TFOs is proposed. 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| subjects | Base Sequence Biochemistry, Molecular Biology Deoxyribonucleases, Type II Site-Specific - chemistry DNA - chemistry Hot Temperature Hydrocarbons Hydrogen-Ion Concentration Hydrolysis Life Sciences Methane - analogs & derivatives Methane - chemistry Models, Molecular Nucleic Acid Conformation Nucleic Acid Heteroduplexes - chemistry Oligodeoxyribonucleotides - chemistry Purine Nucleotides - chemistry Pyrimidine Nucleotides - chemistry Restriction Mapping Spectrophotometry, Ultraviolet Thermodynamics |
| title | Sequence and pH Effects of LNA-Containing Triple Helix-Forming Oligonucleotides: Physical Chemistry, Biochemistry, and Modeling Studies |
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