title: Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair.
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.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Michael R G
authors.initials: MR
authors.lastname: Hodskinson
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Silhan
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Gerry P
authors.initials: GP
authors.lastname: Crossan
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Garaycoechea
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Shivam
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Johnson
authors.affiliation: 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.
authors.forename: Orlando D
authors.initials: OD
authors.lastname: Schärer
authors.affiliation: 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.
authors.forename: Ketan J
authors.initials: KJ
authors.lastname: Patel
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000473:pathology; D018736:DNA Adducts / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004720:Endonucleases / Q000737:chemistry / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000201:enzymology; D009690:Nucleic Acid Conformation; D045522:Recombinases / Q000502:physiology*; D025521:Tumor Suppressor Proteins
chemical_list: D018736:DNA Adducts; D004268:DNA-Binding Proteins; D045522:Recombinases; D025521:Tumor Suppressor Proteins; C095888:xeroderma pigmentosum group F protein; D004720:Endonucleases; C499360:Ercc1 protein, mouse; C543807:Slx4 protein, mouse
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