SUMOylation and PARylation cooperate to recruit and stabilize SLX4 at DNA damage sites

• Published in: EMBO reports 2015-04, Vol.16 (4), p.512-519
• Main Authors: González-Prieto, Román, Cuijpers, Sabine AG, Luijsterburg, Martijn S, van Attikum, Haico, Vertegaal, Alfred CO
• Format: Article
• Language: English
• Subjects: Binding Sites; Cell cycle; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA - genetics; DNA - metabolism; DNA Damage; DNA Repair; EMBO13; EMBO31; Humans; Osteoblasts - cytology; Osteoblasts - metabolism; PARP; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Protein Binding; Protein Processing, Post-Translational; Protein Stability; Protein Transport; Recombinases - genetics; Recombinases - metabolism; Scientific Report; Scientific Reports; Signal Transduction; SLX4; Small Ubiquitin-Related Modifier Proteins - genetics; Small Ubiquitin-Related Modifier Proteins - metabolism; SUMO; Sumoylation; ubiquitin
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201440017

SUMOylation plays important roles in the DNA damage response. However, whether it is important for interstrand crosslink repair remains unknown. We report that the SLX4 nuclease scaffold protein is regulated by SUMOylation. We have identified three SUMO interaction motifs (SIMs) in SLX4, mutating all of which abrogated the binding of SLX4 to SUMO‐2 and covalent SLX4 SUMOylation. An SLX4 mutant lacking functional SIMs is not recruited to PML nuclear bodies nor stabilized at laser‐induced DNA damage sites. Additionally, we elucidated a novel role for PARylation in the recruitment of SLX4 to sites of DNA damage. Combined, our results uncover how SLX4 is regulated by post‐translational modifications. Synopsis SLX4 is crucial for the repair of DNA interstrand crosslinks and maintaining genome stability. This study shows that its recruitment to damaged DNA depends on interaction with SUMO and subsequent SUMOylation, as well as on PARylation. SLX4 is regulated by SUMO‐Interaction Motifs (SIMs). SLX4 SUMOylation occurs during S‐ and G2‐phase of the cell cycle. Mutating the SIMs in SLX4 reduces its accumulation at local sites of DNA damage. SUMOylation enhances SLX4‐mediated resistance to mitomycin C in mouse cells. Graphical Abstract SLX4 is crucial for the repair of DNA interstrand crosslinks and maintaining genome stability. This study shows that its recruitment to damaged DNA depends on interaction with SUMO and subsequent SUMOylation, as well as on PARylation.