Mechanistic Studies on RNA Strand Scission from a C2'-Radical

J Org Chem. 2016 Oct 7;81(19):9199-9205. doi: 10.1021/acs.joc.6b01760. Epub 2016 Sep 26.

Abstract

The C2'-carbon-hydrogen bond in ribonucleotides is significantly weaker than other carbohydrate carbon-hydrogen bonds in RNA or DNA. Independent generation of the C2'-uridine radical (1) in RNA oligonucleotides via Norrish type I photocleavage of a ketone-substituted nucleotide yields direct strand breaks via cleavage of the β-phosphate. The reactivity of 1 in different sequences and under a variety of conditions suggests that the rate constant for strand scission is significantly greater than 106 s-1 at pH 7.2. The initially formed C2'-radical (1) is not trapped under a variety of conditions, consistent with computational studies ( Chem.-Eur. J. 2009 , 15 , 2394 ) that suggest that the barrier to strand scission is very low and that synchronous proton transfer from the 2'-hydroxyl to the departing phosphate group facilitates cleavage. The C2'-radical could be a significant contributor to RNA strand scission by the hydroxyl radical, particularly under anaerobic conditions where 1 can be produced from nucleobase radicals.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carbon / chemistry
  • Hydrogen Bonding
  • Kinetics
  • Mass Spectrometry
  • RNA / chemistry*

Substances

  • RNA
  • Carbon