Stalled transcription complexes promote DNA repair at a distance

Nia M Haines, Young-In T Kim, Abigail J Smith, Nigel J Savery

Research output: Contribution to journalArticle (Academic Journal)peer-review

30 Citations (Scopus)

Abstract

Transcription-coupled nucleotide excision repair (TCR) accelerates the removal of noncoding lesions from the template strand of active genes, and hence contributes to genome-wide variations in mutation frequency. Current models for TCR suppose that a lesion must cause RNA polymerase (RNAP) to stall if it is to be a substrate for accelerated repair. We have examined the substrate requirements for TCR using a system in which transcription stalling and damage location can be uncoupled. We show that Mfd-dependent TCR in bacteria involves the formation of a damage search complex that can detect lesions downstream of a stalled RNAP, and that the strand specificity of the accelerated repair pathway is independent of the requirement for a lesion to stall RNAP. We also show that an ops (operon polarity suppressor) transcription pause site, which causes backtracking of RNAP, can promote the repair of downstream lesions when those lesions do not themselves cause the polymerase to stall. Our findings indicate that the transcription-repair coupling factor Mfd, which is an ATP-dependent superfamily 2 helicase that binds to RNAP, continues to translocate along DNA after RNAP has been displaced until a lesion in the template strand is located. The discovery that pause sites can promote the repair of nonstalling lesions suggests that TCR pathways may play a wider role in modulating mutation frequencies in different parts of the genome than has previously been suspected.

Original languageEnglish
Pages (from-to)4037-42
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number11
DOIs
Publication statusPublished - 18 Mar 2014

Keywords

  • Bacterial Proteins
  • DNA Primers
  • DNA Repair
  • DNA-Directed RNA Polymerases
  • Electrophoretic Mobility Shift Assay
  • Escherichia coli
  • Genome, Bacterial
  • Plasmids
  • Transcription Factors
  • Transcription, Genetic

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