Epigenetic DNA Modification N6-Methyladenine Causes Site-Specific RNA Polymerase II Transcriptional Pausing

J Am Chem Soc. 2017 Oct 18;139(41):14436-14442. doi: 10.1021/jacs.7b06381. Epub 2017 Oct 3.

Abstract

N6-Methyladenine (N6-mA or 6 mA) is an epigenetic DNA modification in eukaryotic genomes. In contrast to the well-established roles of 5-methylcytosine for epigenetic regulation of gene expression, the functional roles of N6-mA remain elusive. In particular, the impact of N6-mA modification of the DNA template on RNA polymerase II (pol II) transcription elongation is not known. In this work, using the Saccharomyces cerevisiae pol II transcriptional elongation system as a model, we investigated the molecular mechanism of pol II recognition and processing of N6-mA sites via both biochemical and structural approaches. We found that N6-mA causes site-specific pol II pausing/stalling. Structural analysis revealed that while N6-mA can reach the +1 template position, the stability of the N6-mA and UTP base pairing is compromised. Taken together, we reveal that the presence of the 6-methyl group on adenine reduces incorporation efficiency and promotes backtracking translocation. Our studies with yeast pol II provide molecular insights into understanding the impacts of N6-mA on pol II transcription dynamics in different organisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / metabolism
  • DNA / chemistry*
  • DNA / metabolism*
  • Epigenesis, Genetic*
  • RNA Polymerase II / metabolism*
  • Saccharomyces cerevisiae / enzymology
  • Transcription, Genetic*

Substances

  • DNA
  • RNA Polymerase II
  • Adenine
  • 6-methyladenine