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RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops

Telomeres which are present at the ends of eukaryotic chromosomes mediate genome stability and determine cellular lifespan(1). Telomeric repeat containing RNAs (TERRA) are long noncoding RNAs transcribed from chromosome ends(2,3), which regulate telomeric chromatin structure and telomere maintenance...

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Autores principales: Feretzaki, Marianna, Pospíšilová, Michaela, Fernandes, Rita Valador, Lunardi, Thomas, Krejci, Lumir, Lingner, Joachim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116795/
https://www.ncbi.nlm.nih.gov/pubmed/33057192
http://dx.doi.org/10.1038/s41586-020-2815-6
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author Feretzaki, Marianna
Pospíšilová, Michaela
Fernandes, Rita Valador
Lunardi, Thomas
Krejci, Lumir
Lingner, Joachim
author_facet Feretzaki, Marianna
Pospíšilová, Michaela
Fernandes, Rita Valador
Lunardi, Thomas
Krejci, Lumir
Lingner, Joachim
author_sort Feretzaki, Marianna
collection PubMed
description Telomeres which are present at the ends of eukaryotic chromosomes mediate genome stability and determine cellular lifespan(1). Telomeric repeat containing RNAs (TERRA) are long noncoding RNAs transcribed from chromosome ends(2,3), which regulate telomeric chromatin structure and telomere maintenance via telomerase and homology directed repair (HDR)(4,5). The mechanisms by which TERRA is recruited to chromosome ends remain poorly defined. Here we develop a reporter system to dissect the underlying mechanisms and demonstrate that the UUAGGG-repeats of TERRA are both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associates with short telomeres through the formation of telomeric DNA:RNA hybrid (R-loop) structures that can form in trans. Telomere association and R-loop formation triggers telomere fragility and is promoted by the RAD51 recombinase and its interacting partner BRCA2 but counteracted by RNA surveillance factors, RNaseH1 and TRF1. RAD51 physically interacts with TERRA and catalyzes R-loop formation with TERRA in vitro supporting a direct involvement of this DNA recombinase in TERRA recruitment by strand invasion. Together, our findings reveal a RAD51-dependent pathway that governs TERRA mediated R-loop formation post transcription providing a mechanism of how lncRNAs can be recruited to new loci in trans.
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spelling pubmed-71167952021-04-14 RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops Feretzaki, Marianna Pospíšilová, Michaela Fernandes, Rita Valador Lunardi, Thomas Krejci, Lumir Lingner, Joachim Nature Article Telomeres which are present at the ends of eukaryotic chromosomes mediate genome stability and determine cellular lifespan(1). Telomeric repeat containing RNAs (TERRA) are long noncoding RNAs transcribed from chromosome ends(2,3), which regulate telomeric chromatin structure and telomere maintenance via telomerase and homology directed repair (HDR)(4,5). The mechanisms by which TERRA is recruited to chromosome ends remain poorly defined. Here we develop a reporter system to dissect the underlying mechanisms and demonstrate that the UUAGGG-repeats of TERRA are both necessary and sufficient to target TERRA to chromosome ends. TERRA preferentially associates with short telomeres through the formation of telomeric DNA:RNA hybrid (R-loop) structures that can form in trans. Telomere association and R-loop formation triggers telomere fragility and is promoted by the RAD51 recombinase and its interacting partner BRCA2 but counteracted by RNA surveillance factors, RNaseH1 and TRF1. RAD51 physically interacts with TERRA and catalyzes R-loop formation with TERRA in vitro supporting a direct involvement of this DNA recombinase in TERRA recruitment by strand invasion. Together, our findings reveal a RAD51-dependent pathway that governs TERRA mediated R-loop formation post transcription providing a mechanism of how lncRNAs can be recruited to new loci in trans. 2020-11-01 2020-10-14 /pmc/articles/PMC7116795/ /pubmed/33057192 http://dx.doi.org/10.1038/s41586-020-2815-6 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Feretzaki, Marianna
Pospíšilová, Michaela
Fernandes, Rita Valador
Lunardi, Thomas
Krejci, Lumir
Lingner, Joachim
RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops
title RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops
title_full RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops
title_fullStr RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops
title_full_unstemmed RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops
title_short RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops
title_sort rad51-dependent recruitment of terra lncrna to telomeres through r-loops
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116795/
https://www.ncbi.nlm.nih.gov/pubmed/33057192
http://dx.doi.org/10.1038/s41586-020-2815-6
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