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)

    Research output: Contribution to journalArticle

    227 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, Ivan M. ; Hain, Karolina ; Declais, Anne-Cecile ; Gardiner, Mary ; Toh, Geraldine W. ; Sanchez-Pulido, Luis ; Heuckmann, Johannes M. ; Toth, Rachel ; Macartney, Thomas ; Eppink, Berina ; Kanaar, Roland ; Ponting, Chris P. ; Lilley, David M. J. ; Rouse, John. / Coordination of Structure-Specific Nucleases by Human SLX4/BTBD12 Is Required for DNA Repair. In: Molecular Cell. 2009 ; Vol. 35, No. 1. pp. 116-127.
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    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.",
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    Munoz, IM, Hain, K, Declais, A-C, Gardiner, M, Toh, GW, Sanchez-Pulido, L, Heuckmann, JM, Toth, R, Macartney, T, Eppink, B, Kanaar, R, Ponting, CP, Lilley, DMJ & Rouse, J 2009, 'Coordination of Structure-Specific Nucleases by Human SLX4/BTBD12 Is Required for DNA Repair', Molecular Cell, vol. 35, no. 1, pp. 116-127. https://doi.org/10.1016/j.molcel.2009.06.020

    Coordination of Structure-Specific Nucleases by Human SLX4/BTBD12 Is Required for DNA Repair. / Munoz, Ivan M.; Hain, Karolina; Declais, Anne-Cecile; Gardiner, Mary; Toh, Geraldine W.; Sanchez-Pulido, Luis; Heuckmann, Johannes M.; Toth, Rachel; Macartney, Thomas; Eppink, Berina; Kanaar, Roland; Ponting, Chris P.; Lilley, David M. J.; Rouse, John (Lead / Corresponding author).

    In: Molecular Cell, Vol. 35, No. 1, 10.07.2009, p. 116-127.

    Research output: Contribution to journalArticle

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    AU - Munoz, Ivan M.

    AU - Hain, Karolina

    AU - Declais, Anne-Cecile

    AU - Gardiner, Mary

    AU - Toh, Geraldine W.

    AU - Sanchez-Pulido, Luis

    AU - Heuckmann, Johannes M.

    AU - Toth, Rachel

    AU - Macartney, Thomas

    AU - Eppink, Berina

    AU - Kanaar, Roland

    AU - Ponting, Chris P.

    AU - Lilley, David M. J.

    AU - Rouse, John

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    KW - NUCLEOTIDE EXCISION-REPAIR

    KW - DOUBLE-STRAND BREAKS

    KW - SACCHAROMYCES-CEREVISIAE

    KW - PROTEIN COMPLEXES

    KW - RECQ HELICASES

    KW - RIBOSOMAL DNA

    KW - RECOMBINATION

    KW - YEAST

    KW - RAD1

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