SUMO conjugation regulates the activity of the Integrator complex

LAUREANO BRAGADO; MELINA MAGALNIK; PABLO MAMMI; AGUSTIN ROMERO; NICOLAS GAIOLI; BERTA POZZI; ANABELLA SREBROW

Oxford

Workshop; RNA 3' end formation and the regulation of eukaryotic genomes; 2022

EMBO

RNA polymerase II (RNAPII) transcribes snRNA genes in close proximity to Cajal bodies,subnuclear compartments that depend on the SUMO isopeptidase USPL1 for their assembly. Weshow here that overexpression of USPL1 as well as of other nuclear SUMO isopeptidase, SENP6,alters snRNA 3’-end cleavage, a process carried out by the Integrator complex. Beyond its rolein snRNA biogenesis, this complex is responsible for regulating the expression of differentRNAPII-transcripts. While several subunits of the complex are SUMO conjugation substrates, wefound that the SUMOylation of INTS11 subunit is regulated by USPL1 and SENP6. We definedLys 381, Lys 462 and Lys 475 as bona fide SUMO attachment sites on INTS11 and observed thatSUMOylation of this protein modulates its sub-cellular localization and is required for Integratoractivity. Moreover, while an INTS11 SUMOylation deficient mutant is still capable of interactingwith INTS4 and INTS9, its interaction with other subunits of the complex is affected. Thesefindings point to a regulatory role of SUMO conjugation on Integrator activity and suggest theinvolvement of INTS11 SUMOylation in the assembly of the complex. Furthermore, this workadds the Integrator-dependent RNA processing to the growing list of cellular processesregulated by SUMO conjugation.