Conserved Pbp1/Ataxin-2 regulates retrotransposon activity and connects polyglutamine expansion-driven protein aggregation to lifespan-controlling rDNA repeats

Lauren A Ostrowski,Karim Mekhail,Christian Krustev,Kevin Zhang,Ashley Wang,Janet N Y Chan,Kirk J Szafranski,Karan J Abraham,Amanda C Hall,Yupeng Liu,Ru Guo,Roxanne Oshidari

doi:10.1038/s42003-018-0187-3

Lauren A Ostrowski, Karim Mekhail + Show 10 more

Open Access

https://doi.org/10.1038/s42003-018-0187-3

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Abstract

Ribosomal DNA (rDNA) repeat instability and protein aggregation are thought to be two major and independent drivers of cellular aging. Pbp1, the yeast ortholog of human ATXN2, maintains rDNA repeat stability and lifespan via suppression of RNA–DNA hybrids. ATXN2 polyglutamine expansion drives neurodegeneration causing spinocerebellar ataxia type 2 and promoting amyotrophic lateral sclerosis. Here, molecular characterization of Pbp1 revealed that its knockout or subjection to disease-modeling polyQ expansion represses Ty1 (Transposons of Yeast) retrotransposons by respectively promoting Trf4-depedendent RNA turnover and Ty1 Gag protein aggregation. This aggregation, but not its impact on retrotransposition, compromises rDNA repeat stability and shortens lifespan by hyper-activating Trf4-dependent turnover of intergenic ncRNA within the repeats. We uncover a function for the conserved Pbp1/ATXN2 proteins in the promotion of retrotransposition, create and describe powerful yeast genetic models of ATXN2-linked neurodegenerative diseases, and connect the major aging mechanisms of rDNA instability and protein aggregation.

Highlights

Ribosomal DNA repeat instability and protein aggregation are thought to be two major and independent drivers of cellular aging
This is especially applicable to transposable elements and ribosomal DNA repeats, which together constitute the majority of repetitive DNA sequences in eukaryotes[9]
Transcription of the full reporter is followed by artificial intron splicing and reverse-transcription of the spliced mRNA into double-stranded cDNA, which is integrated into the genome allowing for HIS3 gene expression (Fig. 1b)[49]

Summary

Introduction

Ribosomal DNA (rDNA) repeat instability and protein aggregation are thought to be two major and independent drivers of cellular aging. Molecular characterization of Pbp[1] revealed that its knockout or subjection to disease-modeling polyQ expansion represses Ty1 (Transposons of Yeast) retrotransposons by respectively promoting Trf4-depedendent RNA turnover and Ty1 Gag protein aggregation This aggregation, but not its impact on retrotransposition, compromises rDNA repeat stability and shortens lifespan by hyperactivating Trf4-dependent turnover of intergenic ncRNA within the repeats. Upon formation and maturation of a virus-like particle, Ty1 mRNA is reverse-transcribed into double-stranded cDNA that associates with integrase and integrates within new loci, including hotspots upstream of RNA Pol III-transcribed genes Like other retroelements such as human LINE-1 (long interspersed nuclear element 1), Ty1 copy number increases with each round of retrotransposition and Ty1 is regulated to ensure genome integrity[12,14,15,16,17,18,19]. Lou Gehrig’s Disease) and/or spinocerebellar ataxia type 2 (SCA2) while expansions beyond 33 Qs are the genetic cause of SCA2 disease[37,38,39,40]

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