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Mol Cell. 2014 May 8;54(3):472-84. doi: 10.1016/j.molcel.2014.03.014. Epub 2014 Apr 10.

Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair.

Author information

1
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
2
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
3
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA.
4
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK; Department of Medicine, Level 5, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: kjp@mrc-lmb.cam.ac.uk.

Abstract

SLX4 binds to three nucleases (XPF-ERCC1, MUS81-EME1, and SLX1), and its deficiency leads to genomic instability, sensitivity to DNA crosslinking agents, and Fanconi anemia. However, it is not understood how SLX4 and its associated nucleases act in DNA crosslink repair. Here, we uncover consequences of mouse Slx4 deficiency and reveal its function in DNA crosslink repair. Slx4-deficient mice develop epithelial cancers and have a contracted hematopoietic stem cell pool. The N-terminal domain of SLX4 (mini-SLX4) that only binds to XPF-ERCC1 is sufficient to confer resistance to DNA crosslinking agents. Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to 100-fold, directing specificity toward DNA forks. Mini-SLX4-XPF-ERCC1 also vigorously stimulates dual incisions around a DNA crosslink embedded in a synthetic replication fork, an essential step in the repair of this lesion. These observations define vertebrate SLX4 as a tumor suppressor, which activates XPF-ERCC1 nuclease specificity in DNA crosslink repair.

PMID:
24726326
PMCID:
PMC4017094
DOI:
10.1016/j.molcel.2014.03.014
[Indexed for MEDLINE]
Free PMC Article
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