Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair

Ivan M Muñoz, Karolina Hain, Anne-Cécile Déclais, Mary Gardiner, Geraldine W Toh, Luis Sanchez-Pulido, Johannes M Heuckmann, Rachel Toth, Thomas Macartney, Berina Eppink, Roland Kanaar, Chris P Ponting, David M J Lilley, John Rouse

Research output: Contribution to journalArticlepeer-review

Abstract

Budding yeast Slx4 interacts with the structure-specific endonuclease Slx1 to ensure completion of ribosomal DNA replication. Slx4 also interacts with the Rad1-Rad10 endonuclease to control cleavage of 3' flaps during repair of double-strand breaks (DSBs). Here we describe the identification of human SLX4, a scaffold for DNA repair nucleases XPF-ERCC1, MUS81-EME1, and SLX1. SLX4 immunoprecipitates show SLX1-dependent nuclease activity toward Holliday junctions and MUS81-dependent activity toward other branched DNA structures. Furthermore, SLX4 enhances the nuclease activity of SLX1, MUS81, and XPF. Consistent with a role in processing recombination intermediates, cells depleted of SLX4 are hypersensitive to genotoxins that cause DSBs and show defects in the resolution of interstrand crosslink-induced DSBs. Depletion of SLX4 causes a decrease in DSB-induced homologous recombination. These data show that SLX4 is a regulator of structure-specific nucleases and that SLX4 and SLX1 are important regulators of genome stability in human cells.

Original languageEnglish
Pages (from-to)116-27
Number of pages12
JournalMolecular Cell
Volume35
Issue number1
DOIs
Publication statusPublished - 10 Jul 2009

Keywords

  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • DNA-Binding Proteins
  • Endonucleases
  • Green Fluorescent Proteins
  • Humans
  • Immunoprecipitation
  • Protein Binding
  • RNA, Small Interfering
  • Recombinases
  • Transfection
  • Two-Hybrid System Techniques

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