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

IM Munoz, K Hain, AC Declais, M Gardiner, GW Toh, L Sanchez-Pulido, JM Heuckmann, R Toth, T Macartney, Berina Eppink, Roland Kanaar, CP Ponting, DMJ Lilley, J Rouse

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267 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 languageUndefined/Unknown
Pages (from-to)116-127
Number of pages12
JournalMolecular Cell
Volume35
Issue number1
DOIs
Publication statusPublished - 2009

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