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Heinz L Sanger - One of the best experts on this subject based on the ideXlab platform.
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secondary structure probing of potato spindle tuber viroid pstvd and sequence comparison with other small pathogenic rna replicons provides evidence for central non Canonical Base pairs large a rich loops and a terminal branch
Journal of Molecular Biology, 1996Co-Authors: Frankulrich Gast, Dirk Kempe, Reiner L Spieker, Heinz L SangerAbstract:Using PCR and in vitro transcription, linear (non-circular) unit-length (+)strand RNA molecules of a lethal PSTVd variant were produced which are able to initiate typical disease symptoms when inoculated into tomato. Non-denaturing gel electrophoresis shows that these transcripts can adopt the same two conformations as circular PSTVd molecules, namely a fast migrating rod-like and a slowly migrating cruciform structure. The rod-like conformer of two end-labelled transcripts was probed with nucleases and dimethyl sulphate, revealing that in solution its right part is identical to computer prediction. In the left part, however, three unique features could be substantiated. (1) In the central region a UV-cross-linkable loop is closed and thus contains non-Canonical Base-pairs ("loop E structure"). (2) Three large "pre-melting loops" are present at 25 degrees to 37 degrees C. The structure of the leftmost one, which is A-rich and conserved in most viroids, correlates with pathogenicity. (3) Two small stem-loops instead of an unbranched structure are found at the left terminus. These hairpins can form in all "large" viroids (approximately 300 nucleotides or longer), thus placing the dodecamer conserved among these viroids, GGUUCCUGUGGU, within the upper helix and the branch junction. A large viroid from Iresine lacks one of these hairpins, whereas all "small" viroids (approximately 300 nucleotides or smaller) lack both. In several plant virus satellite RNAs and the newt satellite RNA, the motif GAUUU(U) and dodecamer remnants appear in an equivalent structure comprising two or three hairpins. Using lead- and terbium-induced cleavage of the RNA, metal binding sites were found, mostly in loops. Thus, probing of PSTVd RNA and comparison with other.
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secondary structure probing of potato spindle tuber viroid pstvd and sequence comparison with other small pathogenic rna replicons provides evidence for central non Canonical Base pairs large a rich loops and a terminal branch
Journal of Molecular Biology, 1996Co-Authors: Frankulrich Gast, Dirk Kempe, Reiner L Spieker, Heinz L SangerAbstract:Abstract Using PCR andin vitrotranscription, linear (non-circular) unit-length (+)strand RNA molecules of a lethal PSTVd variant were produced which are able to initiate typical disease symptoms when inoculated into tomato. Non-denaturing gel electrophoresis shows that these transcripts can adopt the same two conformations as circular PSTVd molecules, namely a fast migrating rod-like and a slowly migrating cruciform structure. The rod-like conformer of two end-labelled transcripts was probed with nucleases and dimethyl sulphate, revealing that in solution its right part is identical to computer prediction. In the left part, however, three unique features could be substantiated. (1) In the central region a UV-cross-link able loop is closed and thus contains non-Canonical Base-pairs (“loop E structure”). (2) Three large “pre-melting loops” are present at 25° to 37°C. The structure of the leftmost one, which is A-rich and conserved in most viroids, correlates with pathogenicity. (3) Two small stem-loops instead of an unbranched structure are found at the left terminus. These hairpins can form in all “large” viroids (≈300 nucleotides or longer), thus placing the dodecamer conserved among these viroids, GGUUCCUGUGGU, within the upper helix and the branch junction. A large viroid fromIresinelacks one of these hairpins, whereas all “small” viroids (≈300 nucleotides or smaller) lack both. In several plant virus satellite RNAs and the newt satellite RNA, the motif GAUUU(U) and dodecamer remnants appear in an equivalent structure comprising two or three hairpins. Using lead- and terbium-induced cleavage of the RNA, metal binding sites were found, mostly in loops. Thus, probing of PSTVd RNA and comparison with other viroids, virusoids, and satellite RNAs contributes to our understanding of the secondary structure of these small pathogenic RNAs.
Frankulrich Gast - One of the best experts on this subject based on the ideXlab platform.
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secondary structure probing of potato spindle tuber viroid pstvd and sequence comparison with other small pathogenic rna replicons provides evidence for central non Canonical Base pairs large a rich loops and a terminal branch
Journal of Molecular Biology, 1996Co-Authors: Frankulrich Gast, Dirk Kempe, Reiner L Spieker, Heinz L SangerAbstract:Using PCR and in vitro transcription, linear (non-circular) unit-length (+)strand RNA molecules of a lethal PSTVd variant were produced which are able to initiate typical disease symptoms when inoculated into tomato. Non-denaturing gel electrophoresis shows that these transcripts can adopt the same two conformations as circular PSTVd molecules, namely a fast migrating rod-like and a slowly migrating cruciform structure. The rod-like conformer of two end-labelled transcripts was probed with nucleases and dimethyl sulphate, revealing that in solution its right part is identical to computer prediction. In the left part, however, three unique features could be substantiated. (1) In the central region a UV-cross-linkable loop is closed and thus contains non-Canonical Base-pairs ("loop E structure"). (2) Three large "pre-melting loops" are present at 25 degrees to 37 degrees C. The structure of the leftmost one, which is A-rich and conserved in most viroids, correlates with pathogenicity. (3) Two small stem-loops instead of an unbranched structure are found at the left terminus. These hairpins can form in all "large" viroids (approximately 300 nucleotides or longer), thus placing the dodecamer conserved among these viroids, GGUUCCUGUGGU, within the upper helix and the branch junction. A large viroid from Iresine lacks one of these hairpins, whereas all "small" viroids (approximately 300 nucleotides or smaller) lack both. In several plant virus satellite RNAs and the newt satellite RNA, the motif GAUUU(U) and dodecamer remnants appear in an equivalent structure comprising two or three hairpins. Using lead- and terbium-induced cleavage of the RNA, metal binding sites were found, mostly in loops. Thus, probing of PSTVd RNA and comparison with other.
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secondary structure probing of potato spindle tuber viroid pstvd and sequence comparison with other small pathogenic rna replicons provides evidence for central non Canonical Base pairs large a rich loops and a terminal branch
Journal of Molecular Biology, 1996Co-Authors: Frankulrich Gast, Dirk Kempe, Reiner L Spieker, Heinz L SangerAbstract:Abstract Using PCR andin vitrotranscription, linear (non-circular) unit-length (+)strand RNA molecules of a lethal PSTVd variant were produced which are able to initiate typical disease symptoms when inoculated into tomato. Non-denaturing gel electrophoresis shows that these transcripts can adopt the same two conformations as circular PSTVd molecules, namely a fast migrating rod-like and a slowly migrating cruciform structure. The rod-like conformer of two end-labelled transcripts was probed with nucleases and dimethyl sulphate, revealing that in solution its right part is identical to computer prediction. In the left part, however, three unique features could be substantiated. (1) In the central region a UV-cross-link able loop is closed and thus contains non-Canonical Base-pairs (“loop E structure”). (2) Three large “pre-melting loops” are present at 25° to 37°C. The structure of the leftmost one, which is A-rich and conserved in most viroids, correlates with pathogenicity. (3) Two small stem-loops instead of an unbranched structure are found at the left terminus. These hairpins can form in all “large” viroids (≈300 nucleotides or longer), thus placing the dodecamer conserved among these viroids, GGUUCCUGUGGU, within the upper helix and the branch junction. A large viroid fromIresinelacks one of these hairpins, whereas all “small” viroids (≈300 nucleotides or smaller) lack both. In several plant virus satellite RNAs and the newt satellite RNA, the motif GAUUU(U) and dodecamer remnants appear in an equivalent structure comprising two or three hairpins. Using lead- and terbium-induced cleavage of the RNA, metal binding sites were found, mostly in loops. Thus, probing of PSTVd RNA and comparison with other viroids, virusoids, and satellite RNAs contributes to our understanding of the secondary structure of these small pathogenic RNAs.
Thenmalarchelvi Rathinavelan - One of the best experts on this subject based on the ideXlab platform.
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Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
Springer Science and Business Media LLC, 2021Co-Authors: Yogeeshwar Ajjugal, Narendar Kolimi, Thenmalarchelvi RathinavelanAbstract:AbstractCGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C Canonical Base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.
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secondary structural choice of dna and rna associated with cgg ccg trinucleotide repeat expansion rationalizes the rna misprocessing in fxtas
Scientific Reports, 2021Co-Authors: Yogeeshwar Ajjugal, Narendar Kolimi, Thenmalarchelvi RathinavelanAbstract:CGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C Canonical Base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.
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conformational distortions induced by periodically recurring a a in d cag d cag provide stereochemical rationale for the trapping of msh2 msh3 in polyq disorders
Computational and structural biotechnology journal, 2021Co-Authors: Yogeeshwar Ajjugal, Thenmalarchelvi RathinavelanAbstract:Abstract CAG repeat instability causes a number of neurodegenerative disorders. The unusual hairpin stem structure formed by the CAG repeats in DNA traps the human mismatch repair MSH2.MSH3 (Mutsβ) complex. To understand the mechanism behind the abnormal binding of Mutsβ with the imperfect hairpin stem structure formed by CAG repeats, molecular dynamics simulations have been carried out for Mutsβ-d(CAG)2(C A G)(CAG)2.d(CTG)2(C A G)(CTG)2 (1 A…A mismatch) and Mutsβ-d(C A G)5.d(C A G)5 (5 mismatches, wherein, A…A occurs periodically) complexes. The interaction of MSH3 residue Tyr245 at the minor groove side of A…A, an essential interaction responsible for the recognition by Mutsβ, are retained in both the cases. Nevertheless, the periodic unwinding caused by the nonisostericity of A…A with the flanking Canonical Base pairs in d(C A G)5.d(C A G)5 distorts the regular B-form geometry. Such an unwinding exposes one of the A…A mismatches (that interacts with Tyr245) at the major groove side and also facilitates the on and off hydrogen bonding interaction with Lys546 sidechain (MSH2-domain-IV). In contrast, kinking of the DNA towards the major groove in Mutsβ-d(CAG)2(C A G)(CAG)2.d(CTG)2(C A G)(CTG)2 doesn’t facilitate such an exposure of the Bases at the major groove. Further, the unwinding of the helix in d(C A G)5.d(C A G)5 enhances the tighter binding between MSH2-domain-I and d(C A G)5.d(C A G)5 at the major groove side as well as between MSH3-domain-I and MSH3-domain-IV. Markedly, such enhanced interactions are absent in Mutsβ-d(CAG)2(CAG)(CAG)2.d(CTG)2(CAG)(CTG)2 that has a single A…A mismatch. Thus, the above-mentioned enhancement in intra- and inter- molecular interactions in Mutsβ-d(C A G)5.d(C A G)5 provide the stereochemical rationale for the trapping of Mutsβ in CAG repeat expansion disorders.
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Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders
'Elsevier BV', 2021Co-Authors: Yogeeshwar Ajjugal, Thenmalarchelvi RathinavelanAbstract:CAG repeat instability causes a number of neurodegenerative disorders. The unusual hairpin stem structure formed by the CAG repeats in DNA traps the human mismatch repair MSH2.MSH3 (Mutsβ) complex. To understand the mechanism behind the abnormal binding of Mutsβ with the imperfect hairpin stem structure formed by CAG repeats, molecular dynamics simulations have been carried out for Mutsβ-d(CAG)2(CAG)(CAG)2.d(CTG)2(CAG)(CTG)2 (1 A…A mismatch) and Mutsβ-d(CAG)5.d(CAG)5 (5 mismatches, wherein, A…A occurs periodically) complexes. The interaction of MSH3 residue Tyr245 at the minor groove side of A…A, an essential interaction responsible for the recognition by Mutsβ, are retained in both the cases. Nevertheless, the periodic unwinding caused by the nonisostericity of A…A with the flanking Canonical Base pairs in d(CAG)5.d(CAG)5 distorts the regular B-form geometry. Such an unwinding exposes one of the A…A mismatches (that interacts with Tyr245) at the major groove side and also facilitates the on and off hydrogen bonding interaction with Lys546 sidechain (MSH2-domain-IV). In contrast, kinking of the DNA towards the major groove in Mutsβ-d(CAG)2(CAG)(CAG)2.d(CTG)2(CAG)(CTG)2 doesn’t facilitate such an exposure of the Bases at the major groove. Further, the unwinding of the helix in d(CAG)5.d(CAG)5 enhances the tighter binding between MSH2-domain-I and d(CAG)5.d(CAG)5 at the major groove side as well as between MSH3-domain-I and MSH3-domain-IV. Markedly, such enhanced interactions are absent in Mutsβ-d(CAG)2(CAG)(CAG)2.d(CTG)2(CAG)(CTG)2 that has a single A…A mismatch. Thus, the above-mentioned enhancement in intra- and inter- molecular interactions in Mutsβ-d(CAG)5.d(CAG)5 provide the stereochemical rationale for the trapping of Mutsβ in CAG repeat expansion disorders
Reiner L Spieker - One of the best experts on this subject based on the ideXlab platform.
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secondary structure probing of potato spindle tuber viroid pstvd and sequence comparison with other small pathogenic rna replicons provides evidence for central non Canonical Base pairs large a rich loops and a terminal branch
Journal of Molecular Biology, 1996Co-Authors: Frankulrich Gast, Dirk Kempe, Reiner L Spieker, Heinz L SangerAbstract:Using PCR and in vitro transcription, linear (non-circular) unit-length (+)strand RNA molecules of a lethal PSTVd variant were produced which are able to initiate typical disease symptoms when inoculated into tomato. Non-denaturing gel electrophoresis shows that these transcripts can adopt the same two conformations as circular PSTVd molecules, namely a fast migrating rod-like and a slowly migrating cruciform structure. The rod-like conformer of two end-labelled transcripts was probed with nucleases and dimethyl sulphate, revealing that in solution its right part is identical to computer prediction. In the left part, however, three unique features could be substantiated. (1) In the central region a UV-cross-linkable loop is closed and thus contains non-Canonical Base-pairs ("loop E structure"). (2) Three large "pre-melting loops" are present at 25 degrees to 37 degrees C. The structure of the leftmost one, which is A-rich and conserved in most viroids, correlates with pathogenicity. (3) Two small stem-loops instead of an unbranched structure are found at the left terminus. These hairpins can form in all "large" viroids (approximately 300 nucleotides or longer), thus placing the dodecamer conserved among these viroids, GGUUCCUGUGGU, within the upper helix and the branch junction. A large viroid from Iresine lacks one of these hairpins, whereas all "small" viroids (approximately 300 nucleotides or smaller) lack both. In several plant virus satellite RNAs and the newt satellite RNA, the motif GAUUU(U) and dodecamer remnants appear in an equivalent structure comprising two or three hairpins. Using lead- and terbium-induced cleavage of the RNA, metal binding sites were found, mostly in loops. Thus, probing of PSTVd RNA and comparison with other.
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secondary structure probing of potato spindle tuber viroid pstvd and sequence comparison with other small pathogenic rna replicons provides evidence for central non Canonical Base pairs large a rich loops and a terminal branch
Journal of Molecular Biology, 1996Co-Authors: Frankulrich Gast, Dirk Kempe, Reiner L Spieker, Heinz L SangerAbstract:Abstract Using PCR andin vitrotranscription, linear (non-circular) unit-length (+)strand RNA molecules of a lethal PSTVd variant were produced which are able to initiate typical disease symptoms when inoculated into tomato. Non-denaturing gel electrophoresis shows that these transcripts can adopt the same two conformations as circular PSTVd molecules, namely a fast migrating rod-like and a slowly migrating cruciform structure. The rod-like conformer of two end-labelled transcripts was probed with nucleases and dimethyl sulphate, revealing that in solution its right part is identical to computer prediction. In the left part, however, three unique features could be substantiated. (1) In the central region a UV-cross-link able loop is closed and thus contains non-Canonical Base-pairs (“loop E structure”). (2) Three large “pre-melting loops” are present at 25° to 37°C. The structure of the leftmost one, which is A-rich and conserved in most viroids, correlates with pathogenicity. (3) Two small stem-loops instead of an unbranched structure are found at the left terminus. These hairpins can form in all “large” viroids (≈300 nucleotides or longer), thus placing the dodecamer conserved among these viroids, GGUUCCUGUGGU, within the upper helix and the branch junction. A large viroid fromIresinelacks one of these hairpins, whereas all “small” viroids (≈300 nucleotides or smaller) lack both. In several plant virus satellite RNAs and the newt satellite RNA, the motif GAUUU(U) and dodecamer remnants appear in an equivalent structure comprising two or three hairpins. Using lead- and terbium-induced cleavage of the RNA, metal binding sites were found, mostly in loops. Thus, probing of PSTVd RNA and comparison with other viroids, virusoids, and satellite RNAs contributes to our understanding of the secondary structure of these small pathogenic RNAs.
Dirk Kempe - One of the best experts on this subject based on the ideXlab platform.
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secondary structure probing of potato spindle tuber viroid pstvd and sequence comparison with other small pathogenic rna replicons provides evidence for central non Canonical Base pairs large a rich loops and a terminal branch
Journal of Molecular Biology, 1996Co-Authors: Frankulrich Gast, Dirk Kempe, Reiner L Spieker, Heinz L SangerAbstract:Using PCR and in vitro transcription, linear (non-circular) unit-length (+)strand RNA molecules of a lethal PSTVd variant were produced which are able to initiate typical disease symptoms when inoculated into tomato. Non-denaturing gel electrophoresis shows that these transcripts can adopt the same two conformations as circular PSTVd molecules, namely a fast migrating rod-like and a slowly migrating cruciform structure. The rod-like conformer of two end-labelled transcripts was probed with nucleases and dimethyl sulphate, revealing that in solution its right part is identical to computer prediction. In the left part, however, three unique features could be substantiated. (1) In the central region a UV-cross-linkable loop is closed and thus contains non-Canonical Base-pairs ("loop E structure"). (2) Three large "pre-melting loops" are present at 25 degrees to 37 degrees C. The structure of the leftmost one, which is A-rich and conserved in most viroids, correlates with pathogenicity. (3) Two small stem-loops instead of an unbranched structure are found at the left terminus. These hairpins can form in all "large" viroids (approximately 300 nucleotides or longer), thus placing the dodecamer conserved among these viroids, GGUUCCUGUGGU, within the upper helix and the branch junction. A large viroid from Iresine lacks one of these hairpins, whereas all "small" viroids (approximately 300 nucleotides or smaller) lack both. In several plant virus satellite RNAs and the newt satellite RNA, the motif GAUUU(U) and dodecamer remnants appear in an equivalent structure comprising two or three hairpins. Using lead- and terbium-induced cleavage of the RNA, metal binding sites were found, mostly in loops. Thus, probing of PSTVd RNA and comparison with other.
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secondary structure probing of potato spindle tuber viroid pstvd and sequence comparison with other small pathogenic rna replicons provides evidence for central non Canonical Base pairs large a rich loops and a terminal branch
Journal of Molecular Biology, 1996Co-Authors: Frankulrich Gast, Dirk Kempe, Reiner L Spieker, Heinz L SangerAbstract:Abstract Using PCR andin vitrotranscription, linear (non-circular) unit-length (+)strand RNA molecules of a lethal PSTVd variant were produced which are able to initiate typical disease symptoms when inoculated into tomato. Non-denaturing gel electrophoresis shows that these transcripts can adopt the same two conformations as circular PSTVd molecules, namely a fast migrating rod-like and a slowly migrating cruciform structure. The rod-like conformer of two end-labelled transcripts was probed with nucleases and dimethyl sulphate, revealing that in solution its right part is identical to computer prediction. In the left part, however, three unique features could be substantiated. (1) In the central region a UV-cross-link able loop is closed and thus contains non-Canonical Base-pairs (“loop E structure”). (2) Three large “pre-melting loops” are present at 25° to 37°C. The structure of the leftmost one, which is A-rich and conserved in most viroids, correlates with pathogenicity. (3) Two small stem-loops instead of an unbranched structure are found at the left terminus. These hairpins can form in all “large” viroids (≈300 nucleotides or longer), thus placing the dodecamer conserved among these viroids, GGUUCCUGUGGU, within the upper helix and the branch junction. A large viroid fromIresinelacks one of these hairpins, whereas all “small” viroids (≈300 nucleotides or smaller) lack both. In several plant virus satellite RNAs and the newt satellite RNA, the motif GAUUU(U) and dodecamer remnants appear in an equivalent structure comprising two or three hairpins. Using lead- and terbium-induced cleavage of the RNA, metal binding sites were found, mostly in loops. Thus, probing of PSTVd RNA and comparison with other viroids, virusoids, and satellite RNAs contributes to our understanding of the secondary structure of these small pathogenic RNAs.