Shelterin Components Modulate Nucleic Acids Condensation and Phase Separation in the Context of Telomeric DNA

Soranno, Andrea; Incicco, J. Jeremías; Bona, Paolo De; Galburt, A. Eric; Holehouse, S. Alex; Galletto, Roberto

doi:10.1016/j.jmb.2022.167685

Cited by 8 publications

(2 citation statements)

References 112 publications

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“…At low force (in the range of 1-4 pN), the fibre abruptly contracted from an extension of about 0.8 μm to the length roughly corresponding to its initial dimension. The relaxation behaviour of the fibre is similar to that observed in recent magnetic tweezer experiments studying TRF2 interactions with telomeric, λ-phage, and mixed-sequence DNAs (Soranno et al, 2022 ). In the cited work, the presence of 300 nM full-length TRF2 resulted in highly heterogeneous stretching and relaxation behaviour under the influence of mechanical force in the range of 0.5–6 pN.…”

Section: Resultssupporting

confidence: 82%

The shelterin component TRF2 mediates columnar stacking of human telomeric chromatin

Wong,

Soman,

Korolev

et al. 2023

EMBO J

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Telomere repeat binding factor 2 (TRF2) is an essential component of the telomeres and also plays an important role in a number of other non-telomeric processes. Detailed knowledge of the binding and interaction of TRF2 with telomeric nucleosomes is limited. Here, we study the binding of TRF2 to in vitro-reconstituted kilobasepair-long human telomeric chromatin fibres using electron microscopy, single-molecule force spectroscopy and analytical ultracentrifugation sedimentation velocity. Our electron microscopy results revealed that full-length and N-terminally truncated TRF2 promote the formation of a columnar structure of the fibres with an average width and compaction larger than that induced by the addition of Mg2+, in agreement with the in vivo observations. Single-molecule force spectroscopy showed that TRF2 increases the mechanical and thermodynamic stability of the telomeric fibres when stretched with magnetic tweezers. This was in contrast to the result for fibres reconstituted on the ‘Widom 601’ high-affinity nucleosome positioning sequence, where minor effects on fibre stability were observed. Overall, TRF2 binding induces and stabilises columnar fibres, which may play an important role in telomere maintenance.

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Section: Resultssupporting

confidence: 82%

The shelterin component TRF2 mediates columnar stacking of human telomeric chromatin

Wong,

Soman,

Korolev

et al. 2023

EMBO J

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“…Many nuclear condensates are associated with specific chromosomal loci, for example, nucleolar organizing region, transcription factories at enhancers, HP1α foci at heterochromatin, and Shelterin at telomeric chromatin. [8][9][10][11] The Smp-lncRNA condensates with LLPS properties may play a novel role in joining two homologous chromosomes during meiotic prophase. To explore the mechanism of Smp-lncRNA condensate formation and its role in homologous chromosome pairing, we here performed in vitro LLPS assays for representative Smps and RNAs.…”

Section: Introductionmentioning

confidence: 99%

The mechanism of homologous chromosome recognition and pairing facilitated by chromosome-tethered protein-RNA condensates

Ding,

Okamasa,

Yoshimura

et al. 2023

Preprint

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Pairing of homologous chromosomes during meiosis is crucial for successful sexual reproduction. Previous studies have shown that the fission yeastsme2RNA, a meiosis-specific long noncoding RNA (lncRNA), accumulates at thesme2locus and plays a key role in mediating robust pairing during meiosis. Several RNA-binding proteins accumulate at thesme2and other lncRNA gene loci in conjunction with the lncRNAs transcribed from these loci. These lncRNA-protein complexes form condensates that exhibit phase separation properties on chromosomes and are necessary for robust pairing of homologous chromosomes. To further understand the mechanisms by which phase separation affects homologous chromosome pairing, we conducted anin vitrophase separation assay with thesme2RNA-associated proteins (Smps) and RNAs. Our research has revealed that one of the Smps, Seb1, exhibits phase separation, which is enhanced by the addition of another Smp, Rhn1, and significantly increased by the addition of purified RNAs. Additionally, we have found that RNAs protect Smp condensates from treatment with 1,6-hexanediol. The Smp condensates containing different types of RNA display distinct FRAP profiles, and the Smp condensates containing the same type of RNA tend to fuse together more efficiently than those containing different types of RNA. Taken together, these results indicate that the RNA species in condensates determine their physical properties and suggest that regional RNA-Smp condensates with distinct properties ensure the pairing of homologous chromosomes.

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Genome maintenance meets mechanobiology

Spegg

Altmeyer

2023

Chromosoma

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Genome stability is key for healthy cells in healthy organisms, and deregulated maintenance of genome integrity is a hallmark of aging and of age-associated diseases including cancer and neurodegeneration. To maintain a stable genome, genome surveillance and repair pathways are closely intertwined with cell cycle regulation and with DNA transactions that occur during transcription and DNA replication. Coordination of these processes across different time and length scales involves dynamic changes of chromatin topology, clustering of fragile genomic regions and repair factors into nuclear repair centers, mobilization of the nuclear cytoskeleton, and activation of cell cycle checkpoints. Here, we provide a general overview of cell cycle regulation and of the processes involved in genome duplication in human cells, followed by an introduction to replication stress and to the cellular responses elicited by perturbed DNA synthesis. We discuss fragile genomic regions that experience high levels of replication stress, with a particular focus on telomere fragility caused by replication stress at the ends of linear chromosomes. Using alternative lengthening of telomeres (ALT) in cancer cells and ALT-associated PML bodies (APBs) as examples of replication stress-associated clustered DNA damage, we discuss compartmentalization of DNA repair reactions and the role of protein properties implicated in phase separation. Finally, we highlight emerging connections between DNA repair and mechanobiology and discuss how biomolecular condensates, components of the nuclear cytoskeleton, and interfaces between membrane-bound organelles and membraneless macromolecular condensates may cooperate to coordinate genome maintenance in space and time.

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Shelterin Components Modulate Nucleic Acids Condensation and Phase Separation in the Context of Telomeric DNA

Cited by 8 publications

References 112 publications

The shelterin component TRF2 mediates columnar stacking of human telomeric chromatin

The shelterin component TRF2 mediates columnar stacking of human telomeric chromatin

The mechanism of homologous chromosome recognition and pairing facilitated by chromosome-tethered protein-RNA condensates

Genome maintenance meets mechanobiology

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