Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses

Stephan Hamperl, Michael J. Bocek, Joshua C. Saldivar, Tomek Swigut, Karlene A. Cimprich

Research output: Contribution to journalArticlepeer-review

163 Scopus citations

Abstract

Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop formation influence genome stability in human cells. R-loops, but not normal transcription complexes, induce DNA breaks and orientation-specific DNA damage responses during conflicts with replication forks. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co-directional (CD) orientation but promoting their formation in the head-on (HO) orientation. Replication stress and deregulated origin firing increase the number of HO collisions leading to genome-destabilizing R-loops. Our findings connect DNA replication to R-loop homeostasis and suggest a mechanistic basis for genome instability resulting from deregulated DNA replication, observed in cancer and other disease states.

Original languageEnglish (US)
Pages (from-to)774-786.e19
JournalCell
Volume170
Issue number4
DOIs
StatePublished - Aug 10 2017
Externally publishedYes

Keywords

  • DNA replication
  • DNA-damage response
  • genome instability
  • R-loops
  • replication stress
  • transcription-replication conflicts

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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