SUMO4 regulates DNA double-strand break repair independently of conjugation

The small ubiquitin-like modifier (SUMO) family is composed of five members, SUMO1, the highly similar SUMO2/SUMO3, SUMO4 and the tissue-specific SUMO5 (SUMO1P1). Sequence variation in SUMO4 is thought to prevent its maturation, resulting in an un-conjugatable SUMO isoform, and consequently, its functions are poorly understood. Here we show for the first time that SUMO4 promotes DNA double-strand break signalling in a manner distinct from SUMO1 or SUMO2/3. We show that SUMO4 function depends on interaction with partner proteins through SUMO interacting motifs and, on its inability, to be conjugated. We show that SUMO4 promotes the activity of the SUMO protease SENP1. In the absence of SUMO4, reduced SENP1 catalytic activity results in hyperSUMOylation that unbalances the recruitment of several DSB repair factors, including RAP80. These data reveal that SUMO4 acts as a buffer for the SUMOylation system.