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m 1 A and m 1 G Potently Disrupt A-RNA Structure Due to the Intrinsic Instability of Hoogsteen Base Pairs

View Article: PubMed Central - PubMed

ABSTRACT

The B-DNA double helix can dynamically accommodate G–C and A–T base pairs in either Watson-Crick or Hoogsteen configurations. Here, we show that G–C+ and A–U Hoogsteen base pairs are strongly disfavored in A-RNA. As a result, N1-methyl adenosine and N1-methyl guanosine, which occur in DNA as a form of alkylation damage, and in RNA as a posttranscriptional modification, have dramatically different consequences. They create G–C+ and A–U Hoogsteen base pairs in duplex DNA that maintain the structural integrity of the double helix, but block base pairing all together and induce local duplex melting in RNA, providing a mechanism for potently disrupting RNA structure through posttranscriptional modifications. The markedly different propensities to form Hoogsteen base pairs in B-DNA and A-RNA may help meet the opposing requirements of maintaining genome stability on one hand, and dynamically modulating the structure of the epitranscriptome on the other.

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Different propensities to form HG bps in B-DNA and A-RNA enable contrasting roles at the genome and transcriptome level. (a) In DNA, m1dA or m1dG damage is absorbed as HG bps that can be recognized by repair enzymes (in red). Had B-DNA lacked the ability to form HG bps, damage could result in duplex melting and genomic instability. In RNA, post-transcriptional modifications resulting in m1rA and m1rG block both WC and HG pairing, melting or modulating RNA secondary structure to favor functional states or effect epigenetic regulation. Had A-RNA had the ability to form HG, the m1rA and m1rG would form HG bps and potentially fail to more significantly alter RNA structure and function. (b) Highly conserved m1rA9 in human mitochondrial tRNALys blocks rA–rU WC base pairing and stabilizes native tRNA structure in which m1rA9 is in a single strand58. The m1rA9 modification would not stabilize native tRNA structure if it were simply absorbed as a HG bp. (c) Highly conserved m1rG37 next to the anti-codon loop37 blocks base pairing between m1rG37 and the first rC in the codon and prevents +1 frameshifting in tRNAPro, which could occur if m1rG37 formed stable HG bp with rC. (d) Proposed mechanism for m1rA enhanced translation through destabilization of secondary structure in the 5′ UTR of mRNA.
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Figure 5: Different propensities to form HG bps in B-DNA and A-RNA enable contrasting roles at the genome and transcriptome level. (a) In DNA, m1dA or m1dG damage is absorbed as HG bps that can be recognized by repair enzymes (in red). Had B-DNA lacked the ability to form HG bps, damage could result in duplex melting and genomic instability. In RNA, post-transcriptional modifications resulting in m1rA and m1rG block both WC and HG pairing, melting or modulating RNA secondary structure to favor functional states or effect epigenetic regulation. Had A-RNA had the ability to form HG, the m1rA and m1rG would form HG bps and potentially fail to more significantly alter RNA structure and function. (b) Highly conserved m1rA9 in human mitochondrial tRNALys blocks rA–rU WC base pairing and stabilizes native tRNA structure in which m1rA9 is in a single strand58. The m1rA9 modification would not stabilize native tRNA structure if it were simply absorbed as a HG bp. (c) Highly conserved m1rG37 next to the anti-codon loop37 blocks base pairing between m1rG37 and the first rC in the codon and prevents +1 frameshifting in tRNAPro, which could occur if m1rG37 formed stable HG bp with rC. (d) Proposed mechanism for m1rA enhanced translation through destabilization of secondary structure in the 5′ UTR of mRNA.

Mentions: The markedly different stability of the A–T/U and G–C+ HG bp in RNA and DNA duplexes provides a basis for achieving opposing functions at the genome and transcriptome levels (Fig. 5a). If DNA did not have a capacity to form HG bps, and instead behaved like RNA, lesions such as m1dA and m1dG that block canonical WC base pairing could greatly destabilize the double helix and potentially cause genomic instability (Fig. 5a). The ability to form HG bps therefore endows DNA with an additional layer of chemical stability over its RNA counterpart that goes beyond resistance to hydrolysis due to the absence of the sugar 2′-OH group. On the other hand, the greater instability of HG bps in A-RNA gives rise to a chemical switch in the form of m1rA and m1rG that can potently modulate RNA structure (Fig. 5a). While it has long been recognized that m1A and m1G can modulate the structure and function of tRNA, rRNA, and other non-coding RNAs37–39,58, this functionality hinges on the unique instability of HG bps in A-RNA uncovered in this work.


m 1 A and m 1 G Potently Disrupt A-RNA Structure Due to the Intrinsic Instability of Hoogsteen Base Pairs
Different propensities to form HG bps in B-DNA and A-RNA enable contrasting roles at the genome and transcriptome level. (a) In DNA, m1dA or m1dG damage is absorbed as HG bps that can be recognized by repair enzymes (in red). Had B-DNA lacked the ability to form HG bps, damage could result in duplex melting and genomic instability. In RNA, post-transcriptional modifications resulting in m1rA and m1rG block both WC and HG pairing, melting or modulating RNA secondary structure to favor functional states or effect epigenetic regulation. Had A-RNA had the ability to form HG, the m1rA and m1rG would form HG bps and potentially fail to more significantly alter RNA structure and function. (b) Highly conserved m1rA9 in human mitochondrial tRNALys blocks rA–rU WC base pairing and stabilizes native tRNA structure in which m1rA9 is in a single strand58. The m1rA9 modification would not stabilize native tRNA structure if it were simply absorbed as a HG bp. (c) Highly conserved m1rG37 next to the anti-codon loop37 blocks base pairing between m1rG37 and the first rC in the codon and prevents +1 frameshifting in tRNAPro, which could occur if m1rG37 formed stable HG bp with rC. (d) Proposed mechanism for m1rA enhanced translation through destabilization of secondary structure in the 5′ UTR of mRNA.
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Figure 5: Different propensities to form HG bps in B-DNA and A-RNA enable contrasting roles at the genome and transcriptome level. (a) In DNA, m1dA or m1dG damage is absorbed as HG bps that can be recognized by repair enzymes (in red). Had B-DNA lacked the ability to form HG bps, damage could result in duplex melting and genomic instability. In RNA, post-transcriptional modifications resulting in m1rA and m1rG block both WC and HG pairing, melting or modulating RNA secondary structure to favor functional states or effect epigenetic regulation. Had A-RNA had the ability to form HG, the m1rA and m1rG would form HG bps and potentially fail to more significantly alter RNA structure and function. (b) Highly conserved m1rA9 in human mitochondrial tRNALys blocks rA–rU WC base pairing and stabilizes native tRNA structure in which m1rA9 is in a single strand58. The m1rA9 modification would not stabilize native tRNA structure if it were simply absorbed as a HG bp. (c) Highly conserved m1rG37 next to the anti-codon loop37 blocks base pairing between m1rG37 and the first rC in the codon and prevents +1 frameshifting in tRNAPro, which could occur if m1rG37 formed stable HG bp with rC. (d) Proposed mechanism for m1rA enhanced translation through destabilization of secondary structure in the 5′ UTR of mRNA.
Mentions: The markedly different stability of the A–T/U and G–C+ HG bp in RNA and DNA duplexes provides a basis for achieving opposing functions at the genome and transcriptome levels (Fig. 5a). If DNA did not have a capacity to form HG bps, and instead behaved like RNA, lesions such as m1dA and m1dG that block canonical WC base pairing could greatly destabilize the double helix and potentially cause genomic instability (Fig. 5a). The ability to form HG bps therefore endows DNA with an additional layer of chemical stability over its RNA counterpart that goes beyond resistance to hydrolysis due to the absence of the sugar 2′-OH group. On the other hand, the greater instability of HG bps in A-RNA gives rise to a chemical switch in the form of m1rA and m1rG that can potently modulate RNA structure (Fig. 5a). While it has long been recognized that m1A and m1G can modulate the structure and function of tRNA, rRNA, and other non-coding RNAs37–39,58, this functionality hinges on the unique instability of HG bps in A-RNA uncovered in this work.

View Article: PubMed Central - PubMed

ABSTRACT

The B-DNA double helix can dynamically accommodate G–C and A–T base pairs in either Watson-Crick or Hoogsteen configurations. Here, we show that G–C+ and A–U Hoogsteen base pairs are strongly disfavored in A-RNA. As a result, N1-methyl adenosine and N1-methyl guanosine, which occur in DNA as a form of alkylation damage, and in RNA as a posttranscriptional modification, have dramatically different consequences. They create G–C+ and A–U Hoogsteen base pairs in duplex DNA that maintain the structural integrity of the double helix, but block base pairing all together and induce local duplex melting in RNA, providing a mechanism for potently disrupting RNA structure through posttranscriptional modifications. The markedly different propensities to form Hoogsteen base pairs in B-DNA and A-RNA may help meet the opposing requirements of maintaining genome stability on one hand, and dynamically modulating the structure of the epitranscriptome on the other.

No MeSH data available.


Related in: MedlinePlus