Abstract
We show that central components of the Fanconi anemia (FA) DNA repair pathway, the tumor suppressor proteins FANCI and FANCD2 (the ID complex), are SUMOylated in response to replication fork stalling. The ID complex is SUMOylated in a manner that depends on the ATR kinase, the FA ubiquitin ligase core complex, and the SUMO E3 ligases PIAS1/PIAS4 and is antagonized by the SUMO protease SENP6. SUMOylation of the ID complex drives substrate selectivity by triggering its polyubiquitylation by the SUMO-targeted ubiquitin ligase RNF4 to promote its removal from sites of DNA damage via the DVC1-p97 ubiquitin segregase complex. Deregulation of ID complex SUMOylation compromises cell survival following replication stress. Our results uncover a regulatory role for SUMOylation in the FA pathway, and we propose that ubiquitin-SUMO signaling circuitry is a mechanism that contributes to the balance of activated ID complex dosage at sites of DNA damage.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins / genetics
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Ataxia Telangiectasia Mutated Proteins / metabolism
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Cell Line, Tumor
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism*
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DNA Damage
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Fanconi Anemia Complementation Group D2 Protein / genetics
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Fanconi Anemia Complementation Group D2 Protein / metabolism*
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Fanconi Anemia Complementation Group Proteins / genetics
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Fanconi Anemia Complementation Group Proteins / metabolism*
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Gene Expression Regulation
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HEK293 Cells
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Humans
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Hydroxyurea / pharmacology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Poly-ADP-Ribose Binding Proteins
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Protein Binding
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Protein Inhibitors of Activated STAT / genetics
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Protein Inhibitors of Activated STAT / metabolism
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Protein Interaction Domains and Motifs
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Small Ubiquitin-Related Modifier Proteins / genetics
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Small Ubiquitin-Related Modifier Proteins / metabolism
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Sumoylation
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Ubiquitin / genetics
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Ubiquitin / metabolism*
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Ubiquitination
Substances
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FANCD2 protein, human
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FANCI protein, human
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Fanconi Anemia Complementation Group D2 Protein
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Fanconi Anemia Complementation Group Proteins
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Nuclear Proteins
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PIAS1 protein, human
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PIAS4 protein, human
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Poly-ADP-Ribose Binding Proteins
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Protein Inhibitors of Activated STAT
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RNF4 protein, human
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Recombinant Fusion Proteins
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Small Ubiquitin-Related Modifier Proteins
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Transcription Factors
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Ubiquitin
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Cysteine Endopeptidases
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SENP6 protein, human
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Hydroxyurea