Article
- The EMBO Journal (2007) 26, 4089 - 4101
- doi:10.1038/sj.emboj.7601838
Published online: 30 August 2007
Subject Categories:
SUMO-targeted ubiquitin ligases in genome stability
John Prudden1, Stephanie Pebernard1, Grazia Raffa2, Daniela A Slavin1, J Jefferson P Perry1,3, John A Tainer1,4, Clare H McGowan1,5 and Michael N Boddy1
- Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA
- Dipartimento di Genetica e Biologia Molecolare, Università di Roma La Sapienza, Rome, Italy
- School of Biotechnology, Amrita Vishwa Vidya Peetham, Amritapuri, Kerala, India
- Life Sciences Division, Department of Molecular Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
- Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
Correspondence to:
Michael N Boddy, Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Tel.: +1 858 784 7042; Fax: +1 858 784 2265; E-mail: nboddy@scripps.edu
Received 10 May 2007; Accepted 30 July 2007
Abstract
We identify the SUMO-Targeted Ubiquitin Ligase (STUbL) family of proteins and propose that STUbLs selectively ubiquitinate sumoylated proteins and proteins that contain SUMO-like domains (SLDs). STUbL recruitment to sumoylated/SLD proteins is mediated by tandem SUMO interaction motifs (SIMs) within the STUbLs N-terminus. STUbL-mediated ubiquitination maintains sumoylation pathway homeostasis by promoting target protein desumoylation and/or degradation. Thus, STUbLs establish a novel mode of communication between the sumoylation and ubiquitination pathways. STUbLs are evolutionarily conserved and include: Schizosaccharomyces pombe Slx8-Rfp (founding member), Homo sapiens RNF4, Dictyostelium discoideum MIP1 and Saccharomyces cerevisiae Slx5–Slx8. Cells lacking Slx8-Rfp accumulate sumoylated proteins, display genomic instability, and are hypersensitive to genotoxic stress. These phenotypes are suppressed by deletion of the major SUMO ligase Pli1, demonstrating the specificity of STUbLs as regulators of sumoylated proteins. Notably, human RNF4 expression restores SUMO pathway homeostasis in fission yeast lacking Slx8-Rfp, underscoring the evolutionary functional conservation of STUbLs. The DNA repair factor Rad60 and its human homolog NIP45, which contain SLDs, are candidate STUbL targets. Consistently, Rad60 and Slx8-Rfp mutants have similar DNA repair defects.
Keywords:
- DNA repair,
- desumoylation,
- STUbL,
- SUMO,
- ubiquitin ligase
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