Phase-separated ribosome-nascent chain complexes in genotoxic stress response

Author:

Németh-Szatmári Orsolya,Nagy-Mikó Bence,Györkei Ádám,Varga Dániel,Kovács Bálint Barna H.,Igaz Nóra,Bognár Bence,Rázga Zsolt,Nagy Gábor,Zsindely Nóra,Bodai László,Papp Balázs,Erdélyi Miklós,Kiricsi Mónika,Blastyák András,Collart Martine A.,Boros Imre M.,Villányi Zoltán

Abstract

Assemblysomes are EDTA- and RNase-resistant ribonucleoprotein (RNP) complexes of paused ribosomes with protruding nascent polypeptide chains. They have been described in yeast and human cells for the proteasome subunit Rpt1, and the disordered amino-terminal part of the nascent chain was found to be indispensable for the accumulation of the Rpt1-RNP into assemblysomes. Motivated by this, to find other assemblysome-associated RNPs we used bioinformatics to rank subunits ofSaccharomyces cerevisiaeprotein complexes according to their amino-terminal disorder propensity. The results revealed that gene products involved in DNA repair are enriched among the top candidates. The Sgs1 DNA helicase was chosen for experimental validation. We found that indeed nascent chains of Sgs1 form EDTA-resistant RNP condensates, assemblysomes by definition. Moreover, upon exposure to UV,SGS1mRNA shifted from assemblysomes to polysomes, suggesting that external stimuli are regulators of assemblysome dynamics. We extended our studies to human cell lines. The BLM helicase, ortholog of yeast Sgs1, was identified upon sequencing assemblysome-associated RNAs from the MCF7 human breast cancer cell line, and mRNAs encoding DNA repair proteins were overall enriched. Using the radiation-resistant A549 cell line, we observed by transmission electron microscopy that 1,6-hexanediol, an agent known to disrupt phase-separated condensates, depletes ring ribosome structures compatible with assemblysomes from the cytoplasm of cells and makes the cells more sensitive to X-ray treatment. Taken together, these findings suggest that assemblysomes may be a component of the DNA damage response from yeast to human.

Funder

Hungarian National Research, Development and Innovation Office

János Bolyai Research Scholarship of the Hungarian Academy of Sciences

Hungarian Brain Research Program

the Swiss National Science Foundation

Publisher

Cold Spring Harbor Laboratory

Subject

Molecular Biology

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