Molecular Mechanisms by Which Oxidative DNA Damage Promotes Telomerase Activity

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2017 Oct 6

PMID 28981887

Citations 43

Authors

Hui-Ting Lee

Arindam Bose

Chun-Ying Lee

Patricia L Opresko

Sua Myong

Affiliations

Soon will be listed here.

Abstract

Telomeres are highly susceptible to oxidative DNA damage, which if left unrepaired can lead to dysregulation of telomere length homeostasis. Here we employed single molecule FRET, single molecule pull-down and biochemical analysis to investigate how the most common oxidative DNA lesions, 8-oxoguanine (8oxoG) and thymine glycol (Tg), regulate the structural properties of telomeric DNA and telomerase extension activity. In contrast to 8oxoG which disrupts the telomeric DNA structure, Tg exhibits substantially reduced perturbation of G-quadruplex folding. As a result, 8oxoG induces high accessibility, whereas Tg retains limited accessibility, of telomeric G-quadruplex DNA to complementary single stranded DNA and to telomere binding protein POT1. Surprisingly, the Tg lesion stimulates telomerase loading and activity to a similar degree as an 8oxoG lesion. We demonstrate that this unexpected stimulation arises from Tg-induced conformational alterations and dynamics in telomeric DNA. Despite impacting structure by different mechanisms, both 8oxoG and Tg enhance telomerase binding and extension activity to the same degree, potentially contributing to oncogenesis.

Citing Articles

Slow G-Quadruplex Conformation Rearrangement and Accessibility Change Induced by Potassium in Human Telomeric Single-Stranded DNA.

Lacen A, Symasek A, Gunter A, Lee H J Phys Chem B. 2024; 128(25):5950-5965.

PMID: 38875355 PMC: 11216195. DOI: 10.1021/acs.jpcb.4c00719.

Dynamic Structures and Fast Transition Kinetics of Oxidized G-Quadruplexes.

Ji J, Sharma A, Pokhrel P, Karna D, Pandey S, Zheng Y Small. 2024; 20(35):e2400485.

PMID: 38678502 PMC: 11357892. DOI: 10.1002/smll.202400485.

Telomere dynamics and oxidative stress in Arabidopsis grown in lunar regolith simulant.

Barcenilla B, Kundel I, Hall E, Hilty N, Ulianich P, Cook J Front Plant Sci. 2024; 15:1351613.

PMID: 38434436 PMC: 10908177. DOI: 10.3389/fpls.2024.1351613.

G-Quadruplexes in Human Telomere: Structures, Properties, and Applications.

Xu Y, Komiyama M Molecules. 2024; 29(1).

PMID: 38202757 PMC: 10780218. DOI: 10.3390/molecules29010174.

BG4 antibody can recognize telomeric G-quadruplexes harboring destabilizing base modifications and lesions.

Johnson S, Paul T, Sanford S, Schnable B, Detwiler A, Thosar S Nucleic Acids Res. 2023; 52(4):1763-1778.

PMID: 38153143 PMC: 10939409. DOI: 10.1093/nar/gkad1209.

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