title: The SMX DNA Repair Tri-nuclease.
abstract: The efficient removal of replication and recombination intermediates is essential for the maintenance of genome stability. Resolution of these potentially toxic structures requires the MUS81-EME1 endonuclease, which is activated at prometaphase by formation of the SMX tri-nuclease containing three DNA repair structure-selective endonucleases: SLX1-SLX4, MUS81-EME1, and XPF-ERCC1. Here we show that SMX tri-nuclease is more active than the three individual nucleases, efficiently cleaving replication forks and recombination intermediates. Within SMX, SLX4 co-ordinates the SLX1 and MUS81-EME1 nucleases for Holliday junction resolution, in a reaction stimulated by XPF-ERCC1. SMX formation activates MUS81-EME1 for replication fork and flap structure cleavage by relaxing substrate specificity. Activation involves MUS81's conserved N-terminal HhH domain, which mediates incision site selection and SLX4 binding. Cell cycle-dependent formation and activation of this tri-nuclease complex provides a unique mechanism by which cells ensure chromosome segregation and preserve genome integrity.
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Haley D M
authors.initials: HD
authors.lastname: Wyatt
authors.affiliation: Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Rob C
authors.initials: RC
authors.lastname: Laister
authors.affiliation: Structural Biology Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.affiliation: Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: stephen.west@crick.ac.uk.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: West
mesh_terms: D002453:Cell Cycle; D004247:DNA / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D042822:Genomic Instability; D006801:Humans; D009097:Multienzyme Complexes; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D045522:Recombinases / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; D045522:Recombinases; C095888:xeroderma pigmentosum group F protein; D004247:DNA; C071447:ERCC1 protein, human; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C498772:MUS81 protein, human; C542320:SLX1 protein, human; C542319:SLX4 protein, human
keywords: DNA repair; DNA replication; Fanconi anemia; Holliday junction; genome stability; homologous recombination; resolution; structure-selective endonuclease