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

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

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
2
Laboratory of Genome Maintenance, Rockefeller University, New York, NY 10065, USA.
3
Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
4
Laboratory of Genome Maintenance, Rockefeller University, New York, NY 10065, USA. Electronic address: agata.smogorzewska@mail.rockefeller.edu.
5
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.

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.

Comment in

PMID:
25533185
PMCID:
PMC4289429
DOI:
10.1016/j.molcel.2014.11.015
[Indexed for MEDLINE]
Free PMC Article

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