Molecular Cell
Volume 57, Issue 1, 8 January 2015, Pages 150-164
Journal home page for Molecular Cell

Article
Ubiquitin-SUMO Circuitry Controls Activated Fanconi Anemia ID Complex Dosage in Response to DNA Damage

https://doi.org/10.1016/j.molcel.2014.12.001Get rights and content
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Highlights

  • The Fanconi anemia ID complex (FANCI/FANCD2) is SUMOylated after DNA damage

  • ID complex SUMOylation is regulated by ATR, the FA core complex, PIAS1/4, and SENP6

  • SUMO-dependent ubiquitylation by RNF4 allows ID complex removal from DNA by DVC1/p97

  • Deregulated ID complex SUMOylation compromises cell survival following DNA damage

Summary

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.

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