Compartmentalization of telomeres through DNA-scaffolded phase separation.

TitleCompartmentalization of telomeres through DNA-scaffolded phase separation.
Publication TypeJournal Article
Year of Publication2022
AuthorsJack, A, Kim, Y, Strom, AR, Lee, DSW, Williams, B, Schaub, JM, Kellogg, EH, Finkelstein, IJ, Ferro, LS, Yildiz, A, Brangwynne, CP
JournalDev Cell
Volume57
Issue2
Pagination277-290.e9
Date Published2022 01 24
ISSN1878-1551
KeywordsCell Line, Chromatin, DNA, DNA Damage, DNA Repair, Humans, Optogenetics, Protein Binding, Shelterin Complex, Telomere, Telomere-Binding Proteins, Telomeric Repeat Binding Protein 1, Telomeric Repeat Binding Protein 2
Abstract

<p>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.</p>

DOI10.1016/j.devcel.2021.12.017
Alternate JournalDev Cell
PubMed ID35077681
PubMed Central IDPMC8988007
Grant ListF31 GM123655 / GM / NIGMS NIH HHS / United States
R35 GM136414 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 GM120554 / GM / NIGMS NIH HHS / United States
U01 DA040601 / DA / NIDA NIH HHS / United States
K99 GM124463 / GM / NIGMS NIH HHS / United States
R00 GM124463 / GM / NIGMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R01 GM118773 / GM / NIGMS NIH HHS / United States