Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance

Mol Cell. 2015 Jan 8;57(1):108-22. doi: 10.1016/j.molcel.2014.11.015. Epub 2014 Dec 18.

Abstract

SLX4, a coordinator of multiple DNA structure-specific endonucleases, is important for several DNA repair pathways. Noncovalent interactions of SLX4 with ubiquitin are required for localizing SLX4 to DNA interstrand crosslinks (ICLs), yet how SLX4 is targeted to other functional contexts remains unclear. Here, we show that SLX4 binds SUMO-2/3 chains via SUMO-interacting motifs (SIMs). The SIMs of SLX4 are dispensable for ICL repair but important for processing CPT-induced replication intermediates, suppressing fragile site instability, and localizing SLX4 to ALT telomeres. The localization of SLX4 to laser-induced DNA damage also requires the SIMs, as well as DNA end resection, UBC9, and MDC1. Furthermore, the SUMO binding of SLX4 enhances its interaction with specific DNA-damage sensors or telomere-binding proteins, including RPA, MRE11-RAD50-NBS1, and TRF2. Thus, the interactions of SLX4 with SUMO and ubiquitin increase its affinity for factors recognizing different DNA lesions or telomeres, helping to direct the SLX4 complex in distinct functional contexts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • DNA Damage
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression Regulation
  • Genome*
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • 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*
  • Telomere / radiation effects
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism*
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*
  • Ultraviolet Rays

Substances

  • Recombinant Fusion Proteins
  • Recombinases
  • SUMO2 protein, human
  • SUMO3 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitin
  • Ubiquitins
  • Ubiquitin-Conjugating Enzymes
  • SLX4 protein, human
  • ubiquitin-conjugating enzyme UBC9