Basic Domain of Telomere Guardian TRF2 Reduces D-loop Unwinding Whereas Rap1 Restores It

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2017 Oct 6

PMID 28981702

Citations 14

Authors

Ivona Necasova

Eliska Janouskova

Tomas Klumpler

Ctirad Hofr

Affiliations

Soon will be listed here.

Abstract

Telomeric repeat binding factor 2 (TRF2) folds human telomeres into loops to prevent unwanted DNA repair and chromosome end-joining. The N-terminal basic domain of TRF2 (B-domain) protects the telomeric displacement loop (D-loop) from cleavage by endonucleases. Repressor activator protein 1 (Rap1) binds TRF2 and improves telomeric DNA recognition. We found that the B-domain of TRF2 stabilized the D-loop and thus reduced unwinding by BLM and RPA, whereas the formation of the Rap1-TRF2 complex restored DNA unwinding. To understand how the B-domain of TRF2 affects DNA binding and D-loop processing, we analyzed DNA binding of full-length TRF2 and a truncated TRF2 construct lacking the B-domain. We quantified how the B-domain improves TRF2's interaction with DNA via enhanced long-range electrostatic interactions. We developed a structural envelope model of the B-domain bound on DNA. The model revealed that the B-domain is flexible in solution but becomes rigid upon binding to telomeric DNA. We proposed a mechanism for how the B-domain stabilizes the D-loop.

Citing Articles

TRF1 and TRF2 form distinct shelterin subcomplexes at telomeres.

Janovic T, Perez G, Schmidt J bioRxiv. 2025; .

PMID: 39763972 PMC: 11703185. DOI: 10.1101/2024.12.23.630076.

Telomere function and regulation from mouse models to human ageing and disease.

Jones-Weinert C, Mainz L, Karlseder J Nat Rev Mol Cell Biol. 2024; .

PMID: 39614014 DOI: 10.1038/s41580-024-00800-5.

Structural biology of shelterin and telomeric chromatin: the pieces and an unfinished puzzle.

Hu H, Yan H, Nguyen T Biochem Soc Trans. 2024; 52(4):1551-1564.

PMID: 39109533 PMC: 7617103. DOI: 10.1042/BST20230300.

TRF2-RAP1 represses RAD51-dependent homology-directed telomere repair by promoting BLM-mediated D-loop unwinding and inhibiting BLM-DNA2-dependent 5'-end resection.

Liang F, Rai R, Sodeinde T, Chang S Nucleic Acids Res. 2024; 52(16):9695-9709.

PMID: 39082275 PMC: 11381343. DOI: 10.1093/nar/gkae642.

Exploring TRF2-Dependent DNA Distortion Through Single-DNA Manipulation Studies.

Zhao X, Vogirala V, Liu M, Zhou Y, Rhodes D, Sandin S Commun Biol. 2024; 7(1):148.

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