Abstract
SummaryTelomeres 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.
Highlights
The nucleus contains the biological software of the cell—the genome—which is organized into individual chromosomes
Telomeres consist of 2–20 kb of double-stranded telomeric TTAGGG repeats followed by 50–200 bases of single-stranded telomeric overhang (Palm and de Lange, 2008)
We propose that Liquid-liquid phase separation (LLPS) of shelterin components builds the telomere compartment and could protect chromosome ends by selectively recruiting telomere-associated factors while limiting access of DNA damage repair (DDR) factors
Summary
The nucleus contains the biological software of the cell—the genome—which is organized into individual chromosomes. Unlike germline cells in which the average telomere length is set, the telomeres in somatic cells shorten over time (Baird et al, 2003; Blackburn, 1991; Harley et al, 1990) This mechanism has been viewed as a tumor-suppressing pathway, as the gradual shortening of telomeres leads to replicative senescence or cell death (Maciejowski and de Lange, 2017). RAP1 binds to the hinge region of TRF2 (Janouskovaet al., 2015; O’Connor et al, 2004) These proteins suppress a wide variety of DDR pathways at telomeres by masking the chromosome ends from being improperly recognized as DNA break sites (Galati et al, 2013; Ray et al, 2014). TRF2 inhibits the ataxia-telangiectasia mutated (ATM) pathway and non-homologous end joining (NHEJ) of telomeres (Okamoto et al, 2013), TRF1 prevents replication fork stalling (Bower and Griffith, 2014; Maestroni et al, 2017), POT1/TPP1 suppresses the ataxia telangiectasia and Rad3-related (ATR) pathway, and TIN2 suppresses ATM, ATR, and NHEJ pathways (Palm and de Lange, 2008)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
