A SUMO-dependent regulatory switch connects the piRNA pathway to the heterochromatin machinery in Drosophila

Abstract

Nuclear Argonaute proteins, guided by small RNAs, mediate sequence-specific heterochromatin formation. The molecular principles that link Argonaute-small RNA complexes to cellular heterochromatin effectors upon binding to nascent target RNAs are poorly understood. Here, we elucidate the mechanism by which the PIWI interacting RNA (piRNA) pathway connects to the heterochromatin machinery in Drosophila. Piwi-mediated stabilization of the corepressor complex SFiNX on chromatin leads to SUMOylation of its subunit Panoramix. SUMOylation, together with an amphipathic LxxLL motif in Panoramix's intrinsically disordered repressor domain, are necessary and sufficient to recruit small ovary (Sov), a multi-zinc finger protein essential for general heterochromatin formation and viability. Structure-guided mutations that abrogate the Panoramix-Sov interaction or that prevent SUMOylation of Panoramix uncouple Sov from the piRNA pathway, resulting in viable but sterile flies in which Piwi-targeted transposons are derepressed. Thus, by coupling recruitment of a corepressor to nascent transcripts with its SUMOylation, Piwi engages the heterochromatin machinery specifically at transposon loci.

Regulation of SUMOylation on RNA metabolism in cancers

“…PIWI interacting RNAs (piRNAs) and long non-coding RNAs (lncRNAs) are also influenced by SUMOylation. Several studies in Drosophila have demonstrated the role of SUMOylation in primary piRNA biogenesis (Muerdter et al, 2013) and piRNA-guided transcriptional silencing and heterochromatin formation (Mugat et al, 2020;Ninova et al, 2020;Andreev et al, 2022;ElMaghraby et al, 2022). Moreover in C. elegans, PIE-1 is itself modified by SUMO and acts as a SUMO E3 together with the conserved SUMO-E3 GEI-17/PAIS1 to promote piRNA-dependent silencing.…”