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

  • Mol Cell. 2009 Jul 10;35(1):116-27. doi: 10.1016/j.molcel.2009.06.020.
Ivan M Muñoz  1 ,  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
Affiliations
  • 1. MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
PMID: 19595721 DOI: 10.1016/j.molcel.2009.06.020
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.