A topological mechanism for TRF2-enhanced strand invasion

Amiard, Simon; Doudeau, M.; Pinte, Sébastien; Poulet, Anaïs; Lenain, Christelle; Faivre-Moskalenko, Cendrine; Angelov, Dimitar; Hug, Nele; Vindigni, Alessandro; Bouvet, Philippe; Paoletti, Jacques; Gilson, Éric; Giraud-Panis, Marie-Josèphe

doi:10.1038/nsmb1192

Cited by 163 publications

(219 citation statements)

References 46 publications

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“…The N-terminal domain of TRF2 has DNA binding activity, which is unspecific to telomeric sequence (5,6). We show that the TRF2 mutant (TRF2 ⌬M ) that contains this unspecific DNAbinding domain and lacks the C-terminal domain stimulates HR when overexpressed.…”

Section: Discussionmentioning

confidence: 95%

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TRF2 is required for repair of nontelomeric DNA double-strand breaks by homologous recombination

Mao

Seluanov

Jiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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TRF2 (telomeric repeat binding factor 2) is an essential component of the telomeric cap, where it forms and stabilizes the T-loop junctions. TRF2 forms the T-loops by stimulating strand invasion of the 3 overhang into duplex DNA. TRF2 also has been shown to localize to nontelomeric DNA double-strand breaks , but its functional role in DNA repair has not been examined. Here, we present evidence that TRF2 is involved in homologous recombination (HR) repair of nontelomeric double-strand breaks. Depletion of TRF2 strongly inhibited HR and delayed the formation of Rad51 foci after ␥-irradiation, whereas overexpression of TRF2 stimulated HR. Depletion of TRF2 had no effect on nonhomologous end-joining, and overexpression of TRF2 inhibited nonhomologous end-joining. We propose, based on our results and on the ability of TRF2 to mediate strand invasion, that TRF2 plays an essential role in HR by facilitating the formation of early recombination intermediates.DNA repair ͉ telomeres T RF2 (telomeric repeat binding factor 2) was first identified as a major telomere binding protein that shields chromosome ends from degradation and from end-to-end fusions (1-3). Mammalian telomeres form large duplex loops in which the single-stranded 3Ј end is embedded within the double-stranded DNA (4). TRF2 generates T-loop structures and recently was shown to bind to DNA junctions (4, 5). The mechanism by which TRF2 facilitates folding of telomeric DNA into T-loops involves binding of TRF2 complexes to DNA and untwisting the neighboring DNA, thereby favoring strand invasion (6).In addition to evidence of TRF2's role in telomere maintenance, there are multiple pieces of evidence that implicate TRF2 in double-strand break (DSB) repair of nontelomeric DNA (7-9). TRF2 localizes to DSB sites at the early stages of cellular response to DSBs, appearing in the first few seconds after DSB induction and leaving as DSBs are being processed (7). TRF2 is phosphorylated by ATM in response to DNA damage (8). The phosphorylated form of TRF2 is not bound to telomeric DNA and is localized to DNA damage sites (8). In turn, overexpression of TRF2 inhibits autophosphorylation of ATM and induction of DNA damage response (9).DSBs are repaired by two major pathways: homologous recombination (HR) and nonhomologous end-joining (NHEJ). During HR, the missing information is copied into the DSB site from a homologous sequence, whereas NHEJ joins the broken ends without homology. Several proteins involved in DSB repair interact with TRF2, such as the MRE11/Rad50/NBS1 complex, Ku70, WRN, and BLM (10-12). Thus, TRF2 is phosphorylated in response to DNA damage, localizes to DNA breaks, and interacts with DSB repair proteins, but its functional role in DSB repair is unknown. Here, we examined the role of TRF2 in DSB repair by HR and NHEJ. ResultsReporter Cell Lines for Detection of NHEJ and HR. To study the role of TRF2 in NHEJ and HR, we used an in vivo assay that measures the repair of an induced chromosomal break. The reporter cassette for detection of NHEJ previously ...

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Section: Discussionmentioning

confidence: 95%

“…TRF2 generates T-loop structures and recently was shown to bind to DNA junctions (4,5). The mechanism by which TRF2 facilitates folding of telomeric DNA into T-loops involves binding of TRF2 complexes to DNA and untwisting the neighboring DNA, thereby favoring strand invasion (6).…”

mentioning

confidence: 99%

TRF2 is required for repair of nontelomeric DNA double-strand breaks by homologous recombination

Mao

Seluanov

Jiang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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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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“…ATM-dependent signalling at telomeres in G2 is required for T-loop re-formation (Verdun et al, 2005;Verdun & Karlseder, 2006). Proteins implicated in homologous recombination (RAD51, RAD52 and XRCC3) and telomeric proteins (TRF2, TRF1 and TIN2) are recruited at telomeres to facilitate T-loop formation after replication (Stansel et al, 2001;de Lange, 2005;Verdun et al, 2005;Verdun & Karlseder, 2006;Amiard et al, 2007, Fouche et al, 2006.…”

Section: Replication Of Telomeresmentioning

confidence: 99%

Differential Effects of the G-Quadruplex Ligand 360A in Human Normal and Cancer Cells

Granotier¹,

Boussin²

2011

DNA Repair and Human Health

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A topological mechanism for TRF2-enhanced strand invasion

Cited by 163 publications

References 46 publications

TRF2 is required for repair of nontelomeric DNA double-strand breaks by homologous recombination

TRF2 is required for repair of nontelomeric DNA double-strand breaks by homologous recombination

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

Differential Effects of the G-Quadruplex Ligand 360A in Human Normal and Cancer Cells

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