TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection

Benarroch-Popivker, Delphine; Pisano, Sabrina; Méndez-Bermúdez, Aarón; Lototska, Liudmyla; Kaur, Parminder; Bauwens, Serge; Djerbi, Nadir; Latrick, Chrysa M; Fraisier, Vincent; Pei, Bei; Gay, Alexandre; Jaune, Emilie; Foucher, Kevin; Cherfils‐Vicini, Julien; Aeby, Eric; Miron, Simona; Londoño-Vallejo, Arturo; Ye, Jing; Du, Marie-Hélène Le; Wang, Hong; Gilson, Éric; Giraud-Panis, Marie-Josèphe

doi:10.1016/j.molcel.2015.12.009

Cited by 133 publications

(173 citation statements)

References 65 publications

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“…5A) and 200-nt DNAs (Fig. 5B) show brighter regions consistent with signals from DNA seen in previous DREEM studies (25)(26)(27). These features are reproducible in multiple scans, scans at different angles, and in trace and retrace images.…”

Section: Ssdna-histone Octamer Complexes Can Be Reconstituted Insupporting

confidence: 84%

“…To simultaneously collect the electrostatic signals, AC and DC biases are applied to a highly doped silicon cantilever with the frequency of the AC bias centered on the first overtone of the cantilever. Taking advantage of the difference in the electrostatic signals from protein and DNA molecules, DREEM reveals the path of DNA in protein-DNA complexes, as it passes around or through proteins (25)(26)(27). Proteins show a greater contrast (darker) than DNA relative to the mica surface, allowing identification of the DNA path in a protein-DNA complex.…”

Section: Ssdna-histone Octamer Complexes Can Be Reconstituted Inmentioning

confidence: 99%

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Nucleosome-like, Single-stranded DNA (ssDNA)-Histone Octamer Complexes and the Implication for DNA Double Strand Break Repair

Adkins

Swygert

Kaur

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuRepair of DNA double strand breaks (DSBs) is key for maintenance of genome integrity. When DSBs are repaired by homologous recombination, DNA ends can undergo extensive processing, producing long stretches of single-stranded DNA (ssDNA). In vivo, DSB processing occurs in the context of chromatin, and studies indicate that histones may remain associated with processed DSBs. Here we demonstrate that histones are not evicted from ssDNA after in vitro chromatin resection. In addition, we reconstitute histone-ssDNA complexes (termed ssNucs) with ssDNA and recombinant histones and analyze these particles by a combination of native gel electrophoresis, sedimentation velocity, electron microscopy, and a recently developed electrostatic force microscopy technique, DREEM (dual-resonance frequency-enhanced electrostatic force microscopy). The reconstituted ssNucs are homogenous and relatively stable, and DREEM reveals ssDNA wrapping around histones. We also find that histone octamers are easily transferred in trans from ssNucs to either double-stranded DNA or ssDNA. Furthermore, the Fun30 remodeling enzyme, which has been implicated in DNA repair, binds ssNucs preferentially over nucleosomes, and ssNucs are effective at activating Fun30 ATPase activity. Our results indicate that ssNucs may be a hallmark of processes that generate ssDNA, and that posttranslational modification of ssNucs may generate novel signaling platforms involved in genome stability.

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Section: Ssdna-histone Octamer Complexes Can Be Reconstituted Insupporting

confidence: 84%

Section: Ssdna-histone Octamer Complexes Can Be Reconstituted Inmentioning

confidence: 99%

Nucleosome-like, Single-stranded DNA (ssDNA)-Histone Octamer Complexes and the Implication for DNA Double Strand Break Repair

Adkins

Swygert

Kaur

et al. 2017

Journal of Biological Chemistry

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“…This therefore suggests that, upon shelterin removal, telomeric DNA remains compacted. TRF2 is able to package telomeric DNA in vitro (Benarroch-Popivker et al 2016), but the lack of this activity upon TRF2 depletion can obviously be compensated for by other factors such as nucleosomes or other proteins that remain unidentified. We also specifically analyzed the sizes of TRF2-depleted telomeres that elicited a DDR.…”

Section: Discussionmentioning

confidence: 99%

The telomeric DNA damage response occurs in the absence of chromatin decompaction

et al. 2017

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Telomeres are specialized nucleoprotein structures that protect chromosome ends from DNA damage response (DDR) and DNA rearrangements. The telomeric shelterin protein TRF2 suppresses the DDR, and this function has been attributed to its abilities to trigger t-loop formation or prevent massive decompaction and loss of density of telomeric chromatin. Here, we applied stochastic optical reconstruction microscopy (STORM) to measure the sizes and shapes of functional human telomeres of different lengths and dysfunctional telomeres that elicit a DDR. Telomeres have an ovoid appearance with considerable plasticity in shape. Examination of many telomeres demonstrated that depletion of TRF2, TRF1, or both affected the sizes of only a small subset of telomeres. Costaining of telomeres with DDR markers further revealed that the majority of DDR signaling telomeres retained a normal size. Thus, DDR signaling at telomeres does not require decompaction. We propose that telomeres are monitored by the DDR machinery in the absence of telomere expansion and that the DDR is triggered by changes at the molecular level in structure and protein composition.

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“…2B) (Griffith et al, 1999;Stansel et al, 2001;Doksani et al, 2013), which sequester the ends of chromosomes and prevent access by the KU complex (de Lange, 2005;Dimitrova and de Lange, 2009). The wrapping of DNA around the TRFH domain of TRF2 has recently been proposed to promote t-loop formation (Amiard et al, 2007;Benarroch-Popivker et al, 2016). TRF2 prevents ATM activation at chromosome termini Verdun et al, 2005), and thus prevents C-NHEJ at telomeres, possibly because of the presence of heterochromatin (Denchi and de Lange, 2007).…”

Section: The Response To Dysfunctional Telomeresmentioning

confidence: 99%

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Muraki

Murnane

2017

Genes Genet. Syst.

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In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini. Telomeres and subtelomeric regions are poor substrates for DNA replication; therefore, regions near telomeres are prone to replication fork stalling and chromosome breakage. Moreover, DSBs near telomeres are poorly repaired. As a result, when DSBs occur near telomeres in normal cells, the cells stop proliferating, while in cancer cells, subtelomeric DSBs induce rearrangements due to the absence of cell cycle checkpoints. The sensitivity of subtelomeric regions to DSBs is due to the improper regulation of processing, because although C-NHEJ is functional at subtelomeric DSBs, excessive processing results in an increased frequency of large deletions and chromosome rearrangements involving A-NHEJ.

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TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection

Cited by 133 publications

References 65 publications

Nucleosome-like, Single-stranded DNA (ssDNA)-Histone Octamer Complexes and the Implication for DNA Double Strand Break Repair

Nucleosome-like, Single-stranded DNA (ssDNA)-Histone Octamer Complexes and the Implication for DNA Double Strand Break Repair

The telomeric DNA damage response occurs in the absence of chromatin decompaction

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

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