The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability

Jean-Hugues Guervilly; Arato Takedachi; Valeria Naim; Sarah Scaglione; Charly Chawhan; Yoann Lovera; Emmanuelle Despras; Isao Kuraoka; Patricia Kannouche; Filippo Rosselli; Pierre-Henri L Gaillard

doi:10.1016/j.molcel.2014.11.014

The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability

Mol Cell. 2015 Jan 8;57(1):123-37. doi: 10.1016/j.molcel.2014.11.014. Epub 2014 Dec 18.

Affiliations

¹ 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.
² 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.
³ Université Paris-Sud, UMR 8200 CNRS, Equipe Labélisée La Ligue Contre le Cancer, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, France.
⁴ Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
⁵ Department of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
⁶ 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.

PMID: 25533188
DOI: 10.1016/j.molcel.2014.11.014

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Cell Line, Tumor
DNA Repair*
DNA Replication
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Gene Expression Regulation
Genome*
Genomic Instability
Humans
Molecular Sequence Data
Protein Binding
Protein Interaction Domains and Motifs
Protein Subunits / genetics
Protein Subunits / metabolism*
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Recombinases / genetics
Recombinases / metabolism*
Sequence Alignment
Signal Transduction
Small Ubiquitin-Related Modifier Proteins / genetics
Small Ubiquitin-Related Modifier Proteins / metabolism*
Sumoylation
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

DNA-Binding Proteins
Protein Subunits
Recombinant Fusion Proteins
Recombinases
Small Ubiquitin-Related Modifier Proteins
xeroderma pigmentosum group F protein
Ubiquitin-Conjugating Enzymes
Ubiquitin-Protein Ligases
SLX4 protein, human
ubiquitin-conjugating enzyme UBC9