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Werner syndrome helicase activity is essential in maintaining fragile site stability
- Source :
- The Journal of Cell Biology
- Publication Year :
- 2008
- Publisher :
- Rockefeller University Press, 2008.
-
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.
- Subjects :
- DNA Replication
Aphidicolin
congenital, hereditary, and neonatal diseases and abnormalities
Werner Syndrome Helicase
Biology
Article
chemistry.chemical_compound
medicine
Humans
education
Research Articles
Werner syndrome
Genetics
education.field_of_study
RecQ Helicases
Chromosome Fragile Sites
Chromosomal fragile site
DNA replication
nutritional and metabolic diseases
Helicase
Cell Biology
Fibroblasts
medicine.disease
Exodeoxyribonucleases
chemistry
Codon, Nonsense
Chromosome Fragile Site
biology.protein
Werner Syndrome
Chromosome breakage
Subjects
Details
- ISSN :
- 15408140 and 00219525
- Volume :
- 180
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Biology
- Accession number :
- edsair.doi.dedup.....178e57eb00c0e060e4dfea6ce9ad80ec