title: Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance.
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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Laboratory of Genome Maintenance, Rockefeller University, New York, NY 10065, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hallet
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Hai Dang
authors.initials: HD
authors.lastname: Nguyen
authors.affiliation: Laboratory of Genome Maintenance, Rockefeller University, New York, NY 10065, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Rickman
authors.affiliation: Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Gill
authors.affiliation: Laboratory of Genome Maintenance, Rockefeller University, New York, NY 10065, USA. Electronic address: agata.smogorzewska@mail.rockefeller.edu.
authors.forename: Agata
authors.initials: A
authors.lastname: Smogorzewska
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: zou.lee@mgh.harvard.edu.
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D016678:Genome; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; 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*; D016615:Telomere / Q000528:radiation effects; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D011993:Recombinant Fusion Proteins; D045522:Recombinases; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D025801:Ubiquitin; D014452:Ubiquitins; D044763:Ubiquitin-Conjugating Enzymes; C542319:SLX4 protein, human; D000098843:Ubiquitin-Conjugating Enzyme UBC9