NMR studies of telomeric nucleoprotein complexes involving the Myb-like domain of the human telomeric protein TRF2

Bilbille, Yann; Paquet, Françoise; Meudal, Hervé; Giraud-Panis, Marie-Josèphe; Lancelot, G.

doi:10.1016/j.crci.2005.06.016

Comptes Rendus. Chimie

2005

DOI: 10.1016/j.crci.2005.06.016

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NMR studies of telomeric nucleoprotein complexes involving the Myb-like domain of the human telomeric protein TRF2

Yann Bilbille

Françoise Paquet

Hervé Meudal

et al.

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Cited by 3 publications

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“…The protein has four distinct regions: the basic N-terminal domain, the TRF homology sequence (residues 45-245), the unstructured linker (residues 246-445), and the DNA-binding domain (residues 446-500) (2). In fact, the structure of the TRF homology sequence, also characterized as a dimerization domain, was determined by X-ray diffraction (9), and the structure of the DNA-binding domain containing a portion of the unstructured linker was determined by NMR and X-ray crystallography (10)(11)(12)(13)(14). Three helices make up the DNAbinding domain.…”

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A Mass Spectrometric Approach to the Study of DNA-Binding Proteins: Interaction of Human TRF2 with Telomeric DNA

et al. 2008

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Human telomeric repeat binding factor 2 (hTRF2) is a protein that plays an important role in capping human telomeres to protect them from DNA damage repair systems. The ineffectiveness of hTRF2 may be linked to aging and cancer. We report the use of PLIMSTEX (protein-ligand interactions by mass spectrometry, titration, and H/D exchange) and selective acetylation of lysine residues to study the interaction of the DNA-binding domain and double-stranded telomeric DNA (repeats of TTAGGG). By increasing the resolution of PLIMSTEX to the peptide level, we localized the changes in deuterium uptake of hTRF2 as a function of varying amounts of a model oligodeoxynucleotide. From these experiments, we determined the affinity constant for binding to DNA, which is within a factor of 3 of the previously reported value. Amide H/D exchange revealed portions of the protein that have contacts with the phosphate backbone of DNA, whereas acetylation disclosed the decrease in solvent accessibility of regions containing Lys 447 and 488, which must be involved in interactions with the DNA major and minor grooves. These complementary approaches of amide H/D exchange and selective side chain modification can be employed effectively to pinpoint and quantify protein-ligand, in particular protein-DNA, interactions.

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A Mass Spectrometric Approach to the Study of DNA-Binding Proteins: Interaction of Human TRF2 with Telomeric DNA

et al. 2008

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Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1

et al. 2010

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Telomeres, the nucleoprotein complexes located at the ends of chromosomes, are involved in chromosome protection and genome stability. Telomeric repeat binding factor 1 (TRF1) and telomeric repeat binding factor 2 (TRF2) are the two telomeric proteins that bind to duplex telomeric DNA through interactions between their C-terminal domain and several guanines of the telomeric tract. Since the antitumour drug cisplatin binds preferentially to two adjacent guanines, we have investigated whether cisplatin adducts could affect the binding of TRF1 and TRF2 to telomeric DNA and the property of TRF2 to stimulate telomeric invasion, a process that is thought to participate in the formation of the t-loop. We show that the binding of TRF1 and TRF2 to telomeric sequences selectively modified by one GG chelate of cisplatin is markedly affected by cisplatin but that the effect is more drastic for TRF2 than for TRF1 (3-5-fold more sensitivity for TRF2 than for TRF1). We also report that platinum adducts cause a decrease in TRF2-dependent stimulation of telomeric invasion in vitro. Finally, in accordance with in vitro data, analysis of telomeric composition after cisplatin treatment reveals that 60% of TRF2 dissociate from telomeres.

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Targeting shelterin proteins for cancer therapy

Brankiewicz-Kopcinska,

Kallingal,

Krzemieniecki

et al. 2024

Drug Discovery Today

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NMR studies of telomeric nucleoprotein complexes involving the Myb-like domain of the human telomeric protein TRF2

Cited by 3 publications

References 25 publications

A Mass Spectrometric Approach to the Study of DNA-Binding Proteins: Interaction of Human TRF2 with Telomeric DNA

A Mass Spectrometric Approach to the Study of DNA-Binding Proteins: Interaction of Human TRF2 with Telomeric DNA

Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1

Targeting shelterin proteins for cancer therapy

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