Nucleoporins cooperate with Polycomb silencers to promote transcriptional repression and repair at DNA double strand breaks

TL;DR

This study shows that nucleoporins work with Polycomb proteins to silence genes near DNA breaks, helping maintain genome stability.

Contribution

The study reveals a novel cooperative mechanism between nucleoporins and Polycomb proteins in DSB-induced gene silencing.

Findings

Disrupting PRC1 clustering disrupts DSB-induced gene silencing.

Nucleoporins like NUP107 and NUP43 localize to DSB sites and are interdependent with PHC2.

NUP107 requires specific structural components for transcriptional repression at DSBs.

Abstract

DNA Double-strand breaks (DSBs) are harmful lesions and major sources of genomic instability. Studies have suggested that DSBs induce local transcriptional silencing that consequently promotes genomic stability. Several factors have been proposed to actively participate in this process, including ATM and Polycomb repressive complex 1 (PRC1). Here we found that disrupting PRC1 clustering disrupts DSB-induced gene silencing. Interactome analysis of PHC2, a PRC1 subunit that promotes the formation of the Polycomb body, found several nucleoporins that constitute the Nuclear Pore Complex (NPC). Similar to PHC2, depleting the nucleoporins also disrupted the DSB-induced gene silencing. We found that some of these nucleoporins, such as NUP107 and NUP43, which are members of the Y-complex of NPC, localize to DSB sites. These nucleoporin-enriched DSBs were distant from the nuclear periphery. The presence of nucleoporins and PHC2 at DSB regions were inter-dependent, suggesting that they act cooperatively in the DSB-induced gene silencing. We further found two structural components within NUP107 to be necessary for the transcriptional repression at DSBs: ATM/ATR-mediated phosphorylation at Serine37 residue within the N-terminal disordered tail, and the NUP133-binding surface at the C-terminus. These results provide a new functional interplay among nucleoporins, ATM and the Polycomb proteins in the DSB metabolism, and underscore their emerging roles in genome stability maintenance.
*Hongseon Song, Yubin Bae, Sangin Kim, and Dante Deascanis contributed equally to this work.