Mechanism of translesion transcription by RNA polymerase II and its role in cellular resistance to DNA damage

Mol Cell. 2012 Apr 13;46(1):18-29. doi: 10.1016/j.molcel.2012.02.006. Epub 2012 Mar 8.


UV-induced cyclobutane pyrimidine dimers (CPDs) in the template DNA strand stall transcription elongation by RNA polymerase II (Pol II). If the nucleotide excision repair machinery does not promptly remove the CPDs, stalled Pol II creates a roadblock for DNA replication and subsequent rounds of transcription. Here we present evidence that Pol II has an intrinsic capacity for translesion synthesis (TLS) that enables bypass of the CPD with or without repair. Translesion synthesis depends on the trigger loop and bridge helix, the two flexible regions of the Pol II subunit Rpb1 that participate in substrate binding, catalysis, and translocation. Substitutions in Rpb1 that promote lesion bypass in vitro increase UV resistance in vivo, and substitutions that inhibit lesion bypass decrease cell survival after UV irradiation. Thus, translesion transcription becomes essential for cell survival upon accumulation of the unrepaired CPD lesions in genomic DNA.

Publication types

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

MeSH terms

  • DNA Damage / radiation effects*
  • DNA Replication / genetics
  • DNA Replication / radiation effects
  • DNA, Fungal / biosynthesis
  • DNA, Fungal / genetics
  • Genome, Fungal / physiology
  • Pyrimidine Dimers / genetics
  • Pyrimidine Dimers / metabolism*
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • Radiation Tolerance / genetics
  • Radiation Tolerance / radiation effects
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Transcription, Genetic / genetics
  • Transcription, Genetic / radiation effects*
  • Ultraviolet Rays / adverse effects*


  • DNA, Fungal
  • Pyrimidine Dimers
  • Saccharomyces cerevisiae Proteins
  • RNA Polymerase II
  • RPB1 protein, S cerevisiae

Associated data

  • PDB/4A93