Werner Syndrome Helicase Activity is Essential in Maintaining Fragile Site Stability

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2008 Jan 23

PMID 18209099

Citations 68

Authors

Livia Maria Pirzio

Pietro Pichierri

Margherita Bignami

Annapaola Franchitto

Affiliations

Soon will be listed here.

Abstract

WRN is a member of the RecQ family of DNA helicases implicated in the resolution of DNA structures leading to the stall of replication forks. Fragile sites have been proposed to be DNA regions particularly sensitive to replicative stress. Here, we establish that WRN is a key regulator of fragile site stability. We demonstrate that in response to mild doses of aphidicolin, WRN is efficiently relocalized in nuclear foci in replicating cells and that WRN deficiency is associated with accumulation of gaps and breaks at common fragile sites even under unperturbed conditions. By expressing WRN isoforms impaired in either helicase or exonuclease activity in defective cells, we identified WRN helicase activity as the function required for maintaining the stability of fragile sites. Finally, we find that WRN stabilizes fragile sites acting in a common pathway with the ataxia telangiectasia and Rad3 related replication checkpoint. These findings provide the first evidence of a crucial role for a helicase in protecting cells against chromosome breakage at normally occurring replication fork stalling sites.

Citing Articles

Phosphorylation-dependent WRN-RPA interaction promotes recovery of stalled forks at secondary DNA structure.

Noto A, Valenzisi P, Di Feo F, Fratini F, Kulikowicz T, Sommers J Nat Commun. 2025; 16(1):997.

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Response to Replication Stress and Maintenance of Genome Stability by WRN, the Werner Syndrome Protein.

Orren D, Machwe A Int J Mol Sci. 2024; 25(15).

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Patterns of Chromosomal Instability and Clonal Heterogeneity in Luminal B Breast Cancer: A Pilot Study.

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WRNIP1 prevents transcription-associated genomic instability.

Valenzisi P, Marabitti V, Pichierri P, Franchitto A Elife. 2024; 12.

PMID: 38488661 PMC: 10942783. DOI: 10.7554/eLife.89981.

Insights into common fragile site instability: DNA replication challenges at DNA repeat sequences.

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