Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair
Copyright policy )Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair
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.
- Cambridge University Hospitals NHS Foundation Trust United Kingdom
- UNIST (Ulsan National Institute of Science and Technology) Korea (Republic of)
- Addenbrooke's Hospital United Kingdom
- MRC Laboratory of Molecular Biology United Kingdom
- Medical Research Council United Kingdom
Base Sequence, DNA Repair, Tumor Suppressor Proteins, Bone Marrow Cells, Mice, Transgenic, Cell Biology, Endonucleases, Hematopoietic Stem Cells, Article, DNA-Binding Proteins, Mice, Inbred C57BL, Recombinases, DNA Adducts, Mice, Neoplasms, Animals, Nucleic Acid Conformation, Molecular Biology, DNA Damage
Base Sequence, DNA Repair, Tumor Suppressor Proteins, Bone Marrow Cells, Mice, Transgenic, Cell Biology, Endonucleases, Hematopoietic Stem Cells, Article, DNA-Binding Proteins, Mice, Inbred C57BL, Recombinases, DNA Adducts, Mice, Neoplasms, Animals, Nucleic Acid Conformation, Molecular Biology, DNA Damage
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