Developmental Cell
Volume 57, Issue 2, 24 January 2022, Pages 277-290.e9
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Article
Compartmentalization of telomeres through DNA-scaffolded phase separation

https://doi.org/10.1016/j.devcel.2021.12.017Get rights and content
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Highlights

  • Telomeres exhibit signatures of multicomponent liquids in cells

  • An optogenetic method controllably induces telomere merger events on demand

  • TRF1 and TRF2 drive phase separation of shelterin with telomeric DNA in vitro

  • Telomeric condensates selectively recruit telomere-associated factors in vitro

Summary

Telomeres form unique nuclear compartments that prevent degradation and fusion of chromosome ends by recruiting shelterin proteins and regulating access of DNA damage repair factors. To understand how these dynamic components protect chromosome ends, we combine in vivo biophysical interrogation and in vitro reconstitution of human shelterin. We show that shelterin components form multicomponent liquid condensates with selective biomolecular partitioning on telomeric DNA. Tethering and anomalous diffusion prevent multiple telomeres from coalescing into a single condensate in mammalian cells. However, telomeres coalesce when brought into contact via an optogenetic approach. TRF1 and TRF2 subunits of shelterin drive phase separation, and their N-terminal domains specify interactions with telomeric DNA in vitro. Telomeric condensates selectively recruit telomere-associated factors and regulate access of DNA damage repair factors. We propose that shelterin mediates phase separation of telomeric chromatin, which underlies the dynamic yet persistent nature of the end-protection mechanism.

Keywords

telomeres
shelterin
phase separation
DNA repair
chromatin organization

Data and code availability

This study did not generate any datasets/code amenable for depositing into public repositories. All data reported in this paper will be shared by the lead contact upon request. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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11

These authors contributed equally

12

Lead contact