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Single-molecule imaging of telomerase RNA reveals a Recruitment-Retention model for telomere elongation

Hadrien Laprade, Emmanuelle Querido, Michael J Smith, David Guerit, Hannah Crimmins, Dimitri Conomos, Emilie Pourret, Pascal Chartrand, Agnel Sfeir
doi: https://doi.org/10.1101/2020.01.31.929026
Hadrien Laprade
Department of Biochemistry and Molecular Medicine, Universite de Montreal, Qc, Canada;
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Emmanuelle Querido
Department of Biochemistry and Molecular Medicine, Universite de Montreal;
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Michael J Smith
NYU School of Medicine;
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David Guerit
Department of Biochemistry and Molecular Medicine, Iniversity of Montreal;
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Hannah Crimmins
NYU School of Medicine;
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Dimitri Conomos
NYU School of Medicine;
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Emilie Pourret
Department of Biochemistry and Molecular Medicine, Universite de Montreal;
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Pascal Chartrand
Department of Biochemistry and Molecular Medicine, Universite de Montreal, Qc, Canada;
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Agnel Sfeir
Skirball Institute of Biomolecular Medicine
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  • For correspondence: agnel.sfeir@med.nyu.edu
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Abstract

Extension of telomeres is a critical step in the immortalization of cancer cells. This complex reaction requires proper spatio-temporal coordination of telomerase and telomeres, and remains poorly understood at the cellular level. To understand how cancer cells execute this process, we combined CRISPR genome editing and MS2 RNA-tagging to image single-molecules of telomerase RNA (hTR). Real-time dynamics and photoactivation experiments of hTR in Cajal bodies (CBs) reveal that hTERT controls the exit of hTR from CBs. Single-molecule tracking of hTR at telomeres shows that TPP1-mediated recruitment results in short telomere-telomerase scanning interactions, then base-pairing between hTR and telomere ssDNA promotes long interactions required for stable telomerase retention. Interestingly, POT1 OB-fold mutations that result in abnormally long telomeres in cancers act by enhancing this retention step. In summary, single-molecule imaging unveils the life-cycle of telomerase RNA and provides a framework to understand how cancer-associated mutations mechanistically drive defects in telomere homeostasis.

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Posted February 02, 2020.
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Single-molecule imaging of telomerase RNA reveals a Recruitment-Retention model for telomere elongation
Hadrien Laprade, Emmanuelle Querido, Michael J Smith, David Guerit, Hannah Crimmins, Dimitri Conomos, Emilie Pourret, Pascal Chartrand, Agnel Sfeir
bioRxiv 2020.01.31.929026; doi: https://doi.org/10.1101/2020.01.31.929026
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Single-molecule imaging of telomerase RNA reveals a Recruitment-Retention model for telomere elongation
Hadrien Laprade, Emmanuelle Querido, Michael J Smith, David Guerit, Hannah Crimmins, Dimitri Conomos, Emilie Pourret, Pascal Chartrand, Agnel Sfeir
bioRxiv 2020.01.31.929026; doi: https://doi.org/10.1101/2020.01.31.929026

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