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

doi:10.1016/j.molcel.2009.06.020

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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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 language	English
Pages (from-to)	116-127
Number of pages	12
Journal	Molecular Cell
Volume	35
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2009.06.020
Publication status	Published - 10 Jul 2009

Keywords

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

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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

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

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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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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N2 - 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.

AB - 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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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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DO - 10.1016/j.molcel.2009.06.020

M3 - Article

C2 - 19595721

SN - 1097-2765

VL - 35

SP - 116

EP - 127

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

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

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Keywords

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