Coordination of Structure-Specific Nucleases by Human SLX4/BTBD12 Is Required for DNA Repair

Ivan M. Munoz, Karolina Hain, Anne-Cecile Declais, 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 (Lead / Corresponding author)

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    238 Citations (Scopus)

    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)116-127
    Number of pages12
    JournalMolecular Cell
    Volume35
    Issue number1
    DOIs
    Publication statusPublished - 10 Jul 2009

    Keywords

    • STRUCTURE-SPECIFIC ENDONUCLEASE
    • NUCLEOTIDE EXCISION-REPAIR
    • DOUBLE-STRAND BREAKS
    • SACCHAROMYCES-CEREVISIAE
    • PROTEIN COMPLEXES
    • RECQ HELICASES
    • RIBOSOMAL DNA
    • RECOMBINATION
    • YEAST
    • RAD1

    Cite this

    Munoz, I. M., Hain, K., Declais, A-C., Gardiner, M., Toh, G. W., Sanchez-Pulido, L., Heuckmann, J. M., Toth, R., Macartney, T., Eppink, B., Kanaar, R., Ponting, C. P., Lilley, D. M. J., & Rouse, J. (2009). Coordination of Structure-Specific Nucleases by Human SLX4/BTBD12 Is Required for DNA Repair. Molecular Cell, 35(1), 116-127. https://doi.org/10.1016/j.molcel.2009.06.020