Document Detail


Perturbed replication induced genome-wide or at common fragile sites is differently managed in the absence of WRN.
MedLine Citation:
PMID:  22689923     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The Werner syndrome protein (WRN) is a member of the RecQ helicase family. Loss of WRN results in a human disease, the Werner syndrome (WS), characterised by high genomic instability, elevated cancer risk and premature aging. WRN is crucial for the recovery of stalled replication forks and possesses both helicase and exonuclease enzymatic activities of uncertain biological significance. Previous work revealed that WRN promotes formation of MUS81-dependent double strand breaks (DSBs) at HU-induced stalled forks, allowing replication restart at the expense of chromosome stability. Here, using cells expressing the helicase- or exonuclease-dead WRN mutant, we show that both activities of WRN are required to prevent MUS81-dependent breakage after HU-induced replication arrest. Moreover, we provide evidence that, in WS cells, DSBs generated by MUS81 do not require RAD51 activity for their formation. Surprisingly, when replication is specifically perturbed at common fragile sites (CFS) by aphidicolin, WRN limits accumulation of ssDNA gaps and no MUS81-dependent DSBs are detected. However, in both cases, RAD51 is essential to ensure viability of WS cells, though by different mechanisms. Thus, the role of WRN in response to perturbation of replication along CFS is functionally distinct from that carried out at stalled forks genome-wide. Our results contribute to unveil two different mechanisms used by the cell to overcome the absence of WRN.
Authors:
Ivana Murfuni; Anita De Santis; Maurizio Federico; Margherita Bignami; Pietro Pichierri; Annapaola Franchitto
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-11
Journal Detail:
Title:  Carcinogenesis     Volume:  -     ISSN:  1460-2180     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Istituto Superiore di Santità, Dipartimento Ambiente e Connessa Prevenzione Primaria, Rome, Italy.
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