SUMO4 promotes SUMO deconjugation required for DNA double-strand break repair.

The amplitudes of small-modifier protein signalling through ubiquitin and the Small Ubiquitin-like Modifiers, SUMO1-3, are critical to the correct phasing of DNA repair protein accumulation, activity, and clearance, and for the completion of mammalian DNA double-strand break (DSB) repair. However, how SUMO-conjugate signalling in the response is delineated is poorly understood. At the same time, the role of the non-conjugated SUMO protein, SUMO4, has remained enigmatic. Here we reveal that SUMO4 is required to prevent excessive DNA-damage-induced SUMOylation and deleterious over-accumulation of RAP80. Mechanistically we show SUMO4 acts independently of its conjugation and potentiates SENP1 catalytic activity. These data identify SUMO4 as a SUMO deconjugation component and show SUMO4:SENP1 are critical regulators of DNA-damage-induced SUMO signalling. HighlightsO_LIThe roles of the SUMO family members, SUMO1-4, in DSB repair are not redundant. C_LIO_LISUMO4 conjugation is deleterious. C_LIO_LISUMO4 promotes SENP1 catalytic activity. C_LIO_LISUMO4:SENP1 restrict SUMO-signalling and accumulation of the BRCA1-A complex. C_LI