Sae2/CtIP prevents R-loop accumulation in eukaryotic cells

Nodar Makharashvili, Sucheta Arora, Yizhi Yin, Qiong Fu, Xuemei Wen, Ji Hoon Lee, Chung Hsuan Kao, Justin W.C. Leung, Kyle M. Miller, Tanya T. Paull

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

The Sae2/CtIP protein is required for efficient processing of DNA double-strand breaks that initiate homologous recombination in eukaryotic cells. Sae2/CtIP is also important for survival of single-stranded Top1-induced lesions and CtIP is known to associate directly with transcription-associated complexes in mammalian cells. Here we investigate the role of Sae2/CtIP at single-strand lesions in budding yeast and in human cells and find that depletion of Sae2/CtIP promotes the accumulation of stalled RNA polymerase and RNA-DNA hybrids at sites of highly expressed genes. Overexpression of the RNA-DNA helicase Senataxin suppresses DNA damage sensitivity and R-loop accumulation in Sae2/CtIP-deficient cells, and a catalytic mutant of CtIP fails to complement this sensitivity, indicating a role for CtIP nuclease activity in the repair process. Based on this evidence, we propose that R-loop processing by 5’ flap endonucleases is a necessary step in the stabilization and removal of nascent R-loop initiating structures in eukaryotic cells.

Original languageEnglish (US)
Article numbere42733
JournaleLife
Volume7
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience

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