Oxidative stress at telomeres triggers internal DNA loops, TRF1 dissociation, and TRF2-dependent R-loops

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(7)

Published: April 10, 2025

Telomeres are the nucleoprotein structures at chromosome ends. particularly sensitive to oxidative stress, which can induce telomere damage, shortening, and premature cellular senescence. How damage influences structure has not been defined. Here, we telomeres using menadione, damages mitochondria mimicking intrinsic stress. We find that stress induces single-stranded DNA breaks, internal loop structures, dissociation of shelterin component TRF1, upregulation TERRA long noncoding RNA, increased DNA:RNA hybrid known as R-loops. R-loop formation is enhanced only in cis telomeres, show transcription, but also trans transcription induced indicating post-transcriptional formation. Finally, requires TRF2, whose promoting activity may be unleashed upon TRF1 from telomeres. Altogether, our findings uncover response major remodelling telomeric DNA, complexes, they unravel a physiological role TRF2's ability stimulate propose identified structural changes facilitate signalling repair pathways maintain integrity during development aging.

Language: Английский

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Locking the gates of immortality: targeting alternative lengthening of telomeres (ALT) pathways

Medical Oncology, Journal Year: 2025, Volume and Issue: 42(3)

Published: Feb. 18, 2025

Language: Английский

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R-loop homeostasis in genome dynamics, gene expression and development

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 92, P. 102325 - 102325

Published: March 4, 2025

Language: Английский

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Cancer-associated DAXX mutations reveal a critical role for ATRX localization in ALT suppression

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Abstract To maintain genome stability, proliferating cells must enact a program of telomere maintenance. While most tumors telomeres through the action telomerase, subset utilize DNA-templated process termed Alternative Lengthening Telomeres or ALT. ALT is associated with mutations in ATRX/DAXX/H3.3 histone chaperone complex, which responsible for deposition non-replicative variant H3.3 at heterochromatic regions including telomeres. We wished to better understand role DAXX plays suppression, and determine disease-associated are unable suppress answer this question, we have leveraged G292 cell line, ATRX wild type but has undergone fusion event non-canonical kinesin KIFC3. Restoration wild-type localizes abrogates Using model system, tested ability panel missense variants Missense binding domain, C-terminal SUMO interaction motif reduce Unexpectedly, find that domain lead failure localization. conclude key function suppression localization nuclear foci.

Language: Английский

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Identification of modulators of the ALT pathway through a native FISH-based optical screen

Cell Reports, Journal Year: 2024, Volume and Issue: 44(1), P. 115114 - 115114

Published: Dec. 26, 2024

Language: Английский

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