Ubiquitylation and SUMOylation Control DNA Damage Repair Complex Balance

The Fanconi anemia (FA) pathway, which detects and repairs DNA interstrand crosslinks, is highly regulated by posttranslational modifications. Although FA-associated proteins are functionally modified via phosphorylation and monoubiquitylation, additional mechanisms have also been suggested to regulate this pathway. Gibbs-Seymour and colleagues found that Fanconi anemia, complementation group I (FANCI) and FANCD2, which comprise the ID complex, were SUMOylated in response to DNA damage, which triggered polyubiquitylation and subsequent extraction of the ID complex from sites of DNA damage. ID complex SUMOylation occurred exclusively on chromatin in response to genotoxic stresses, in particular agents that cause replication fork stalling. Deletion studies and in vitro SUMOylation assays identified protein inhibitor of activated STAT1 (PIAS1) and PIAS4 as the primary SUMO E3 ligases responsible for this modification. Additionally, both ATR-mediated phosphorylation and monoubiquitylation of the ID complex were required for its SUMOylation, which was antagonized by sentrin-specific peptidase 6 (SENP6). SUMOylation resulted in recruitment of the SUMO-targeted ubiquitin ligase ring finger protein 4 (RNF4), which polyubiquitylated the ID complex with both K48- and K63-linked moieties. Perturbation of RNF4 levels or activity resulted in increased FANCI and FANCD2 levels at sites of DNA damage, indicating that SUMO-dependent polyubiquitylation of the ID complex limits its accumulation at DNA lesions. Consistent with this idea, ubiquitylation of the SUMOylated ID complex promoted its extraction from stalled replication forks by the ubiquitin-dependent DVC1 (also known as SprT-like N-terminal domain 1)–p97 segregase complex. Mutation of SUMOylation sites on FANCI inhibited DVC1–p97-mediated removal of the ID complex and failed to rescue sensitivity to genotoxic stress in FANCI-deficient cells, supporting the hypothesis that initial SUMOylation of FANCI is critical to control ID complex occupancy at sites of DNA damage. Overall, these data indicate that SUMOylation of the ID complex regulates its dosage at DNA lesions to promote genome stability.

Gibbs-Seymour I, Oka Y, Rajendra E, Weinert BT, Passmore LA, Patel KJ, et al. Ubiquitin-SUMO Circuitry controls activated Fanconi anemia ID complex dosage in response to DNA damage. Mol Cell 2015;57:150–64.

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