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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 publication

DOI

10.1016/j.molcel.2009.06.020

Type

Journal article

Journal

Mol Cell

Publication Date

10/07/2009

Volume

35

Pages

116 - 127

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