Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination

Mol Cell. 2011 Jun 24;42(6):794-805. doi: 10.1016/j.molcel.2011.04.026.

Abstract

We present a molecular dissection of pause site-dependent transcriptional termination for mammalian RNA polymerase II (Pol II)-transcribed genes. We show that nascent transcripts form RNA/DNA hybrid structures (R-loops) behind elongating Pol II and are especially prevalent over G-rich pause sites positioned downstream of gene poly(A) signals. Senataxin, a helicase protein associated with AOA2/ALS4 neurodegenerative disorders, acts to resolve these R-loop structures and by so doing allows access of the 5'-3' exonuclease Xrn2 at 3' cleavage poly(A) sites. This affords 3' transcript degradation and consequent Pol II termination. In effect, R-loops formed over G-rich pause sites, followed by their resolution by senataxin, are key steps in the termination process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DNA / chemistry
  • DNA / genetics
  • DNA / metabolism*
  • Exoribonucleases / metabolism*
  • HeLa Cells
  • Humans
  • Nucleic Acid Heteroduplexes / chemistry
  • Nucleic Acid Hybridization
  • RNA / chemistry
  • RNA / genetics
  • RNA / metabolism*
  • RNA Helicases / metabolism*
  • Transcription, Genetic*

Substances

  • Nucleic Acid Heteroduplexes
  • RNA
  • DNA
  • Exoribonucleases
  • XRN2 protein, human
  • SETX protein, human
  • RNA Helicases