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PMID:19595721

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Citation

Muñoz, IM, Hain, K, Déclais, AC, Gardiner, M, Toh, GW, Sanchez-Pulido, L, Heuckmann, JM, Toth, R, Macartney, T, Eppink, B, Kanaar, R, Ponting, CP, Lilley, DM and Rouse, J (2009) Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol. Cell 35:116-27

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.

Links

PubMed Online version:10.1016/j.molcel.2009.06.020

Keywords

Blotting, Western; Cell Line; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Repair; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Endonucleases/genetics; Endonucleases/metabolism; Green Fluorescent Proteins/genetics; Green Fluorescent Proteins/metabolism; Humans; Immunoprecipitation; Protein Binding; RNA, Small Interfering/genetics; Recombinases/genetics; Recombinases/metabolism; Transfection; Two-Hybrid System Techniques

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SLX4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92889

F

Seeded From UniProt

complete

HUMAN:SLX4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BQ83

F

Seeded From UniProt

complete

HUMAN:SLX4

involved_in

GO:0000724: double-strand break repair via homologous recombination

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SLX4

involved_in

GO:0010792: DNA double-strand break processing involved in repair via single-strand annealing

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SLX4

part_of

GO:0033557: Slx1-Slx4 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SLX4

colocalizes_with

GO:0048476: Holliday junction resolvase complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SLX4

colocalizes_with

GO:0070522: ERCC4-ERCC1 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:XPF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IY92

F

Seeded From UniProt

complete

HUMAN:SLX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IY92

F

Seeded From UniProt

complete

HUMAN:SLX1

involved_in

GO:0000724: double-strand break repair via homologous recombination

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SLX1

involved_in

GO:0006281: DNA repair

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SLX1

involved_in

GO:0010792: DNA double-strand break processing involved in repair via single-strand annealing

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SLX1

part_of

GO:0033557: Slx1-Slx4 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SLX1

enables

GO:0008821: crossover junction endodeoxyribonuclease activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MUS81

enables

GO:0048257: 3'-flap endonuclease activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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