SUMO conjugation regulates the activity of the Integrator complex

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

NUCLEIC ACIDS RESEARCH

OXFORD UNIV PRESS

Lugar: Oxford; Año: 2022

0305-1048

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. We show 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 role in snRNA biogenesis, this complex is responsible for regulating the expression of different RNAPII-transcripts. While several subunits of the complex are SUMO conjugation substrates, we found that the SUMOylation of INTS11 subunit is regulated by USPL1 and SENP6. We defined Lys 381, Lys 462 and Lys 475 as bona fide SUMO attachment sites on INTS11 and observed that SUMOylation of this protein modulates its sub-cellular localization and is required for Integrator activity. Moreover, while an INTS11 SUMOylation deficient mutant is still capable of interacting with INTS4 and INTS9, its interaction with other subunits of the complex is affected. These findings point to a regulatory role of SUMO conjugation on Integrator activity and suggest the involvement of INTS11 SUMOylation in the assembly of the complex. Furthermore, this work adds the Integrator-dependent RNA processing to the growing list of cellular processes regulated by SUMO conjugation.