title: The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability.
abstract: The SLX4 Fanconi anemia protein is a tumor suppressor that may act as a key regulator that engages the cell into specific genome maintenance pathways. Here, we show that the SLX4 complex is a SUMO E3 ligase that SUMOylates SLX4 itself and the XPF subunit of the DNA repair/recombination XPF-ERCC1 endonuclease. This SLX4-dependent activity is mediated by a remarkably specific interaction between SLX4 and the SUMO-charged E2 conjugating enzyme UBC9 and relies not only on newly identified SUMO-interacting motifs (SIMs) in SLX4 but also on its BTB domain. In contrast to its ubiquitin-binding UBZ4 motifs, SLX4 SIMs are dispensable for its DNA interstrand crosslink repair functions. Instead, while detrimental in response to global replication stress, the SUMO E3 ligase activity of the SLX4 complex is critical to prevent mitotic catastrophe following common fragile site expression.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Inserm-Unité 1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, F-13009 Marseille, France; Aix-Marseille Université, F-13284 Marseille, France. Electronic address: jean-hugues.guervilly@inserm.fr.
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Guervilly
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Inserm-Unité 1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, F-13009 Marseille, France; Aix-Marseille Université, F-13284 Marseille, France.
authors.forename: Arato
authors.initials: A
authors.lastname: Takedachi
authors.affiliation: Université Paris-Sud, UMR 8200 CNRS, Equipe Labélisée La Ligue Contre le Cancer, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Valeria
authors.initials: V
authors.lastname: Naim
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Inserm-Unité 1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, F-13009 Marseille, France; Aix-Marseille Université, F-13284 Marseille, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Scaglione
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Charly
authors.initials: C
authors.lastname: Chawhan
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Inserm-Unité 1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, F-13009 Marseille, France; Aix-Marseille Université, F-13284 Marseille, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Lovera
authors.affiliation: Université Paris-Sud, UMR 8200 CNRS, Equipe Labélisée La Ligue Contre le Cancer, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Despras
authors.affiliation: Department of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Kuraoka
authors.affiliation: Université Paris-Sud, UMR 8200 CNRS, Equipe Labélisée La Ligue Contre le Cancer, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kannouche
authors.affiliation: Université Paris-Sud, UMR 8200 CNRS, Equipe Labélisée La Ligue Contre le Cancer, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Inserm-Unité 1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, F-13009 Marseille, France; Aix-Marseille Université, F-13284 Marseille, France. Electronic address: pierre-henri.gaillard@inserm.fr.
authors.forename: Pierre-Henri L
authors.initials: PHL
authors.lastname: Gaillard
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D016678:Genome; D042822:Genomic Instability; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D045522:Recombinases / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D004268:DNA-Binding Proteins; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D045522:Recombinases; D025841:Small Ubiquitin-Related Modifier Proteins; C095888:xeroderma pigmentosum group F protein; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; C542319:SLX4 protein, human; D000098843:Ubiquitin-Conjugating Enzyme UBC9