Noncovalent Interactions with SUMO and Ubiquitin Orchestrate Distinct Functions of the SLX4 Complex in Genome Maintenance

Jian Ouyang, Elizabeth Garner, Alexander Hallet, Hai Dang Nguyen, Kimberly A. Rickman, Grace Gill, Agata Smogorzewska, Lee Zou

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)108-122
Number of pages15
JournalMolecular Cell
Volume57
Issue number1
DOIs
StatePublished - Jan 8 2015
Externally publishedYes

Bibliographical note

Funding Information:
We thank Drs. R. Baer, R. Hay, T. Hunter, and J. Jin for reagents, and members of the Zou lab for helpful discussions. L.Z. is a Jim & Ann Orr Massachusetts General Hospital Research Scholar. A.S. is a Rita Allen Foundation scholar, an Irma T. Hirschl scholar, an Alexandrine and Alexander Sinsheimer Foundation scholar, and a recipient of a Doris Duke Clinical Scientist Development Award. E.G. is a recipient of the Women & Science fellowship from The Rockefeller University. K.A.R. was supported by the NIH Training Program grant T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. This work was supported by grants from NIH (GM076388 to L.Z. and R01HL120922 to A.S.), the Federal Share of MGH Proton Program (L.Z.), the Burroughs Wellcome Fund Career Award for Medical Scientists (A.S.), and the Doris Duke Charitable Foundation (A.S.).

Publisher Copyright:
© 2015 Elsevier Inc.

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