Document Detail


Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1.
MedLine Citation:
PMID:  22447567     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PARP inhibitors are currently being used in clinical trials to treat BRCA1- or BRCA2-defective tumors, based on the synthetic lethal interaction between PARP1 and BRCA1/2-mediated homologous recombination (HR). However, the molecular mechanisms that drive this synthetic lethality remain unclear. Here, we show increased levels of Mre11, a key component of MRN (Mre11-Rad50-Nbs1) complex that plays a role in the restart of stalled replication forks and enhanced resection at stalled replication forks in BRCA2-deficient cells. BRCA2-deficient cells also showed hypersensitivity to the Mre11 inhibitor mirin. Interestingly, PARP1 activity was required to protect stalled forks from Mre11-dependent degradation. Resistance to PARP inhibition in BRCA2-mutant cells led to reduced levels of Mre11 foci and also rescued their sensitivity to mirin. Taken together, our findings not only show that Mre11 activity is required for the survival of BRCA2 mutant cells but also elucidate roles for both the BRCA2 and PARP1 proteins in protecting stalled replication forks, which offers insight into the molecular mechanisms of the synthetic lethality between BRCA2 and PARP1.
Authors:
Songmin Ying; Freddie C Hamdy; Thomas Helleday
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-23
Journal Detail:
Title:  Cancer research     Volume:  72     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-04     Completed Date:  2012-08-10     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2814-21     Citation Subset:  IM    
Copyright Information:
©2012 AACR
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MeSH Terms
Descriptor/Qualifier:
BRCA2 Protein / physiology*
Cell Proliferation
DNA Replication*
DNA-Binding Proteins / antagonists & inhibitors,  physiology*
Humans
Poly(ADP-ribose) Polymerases / antagonists & inhibitors,  physiology*
Pyrimidinones / pharmacology
Thiones / pharmacology
Grant Support
ID/Acronym/Agency:
G0700730//Medical Research Council
Chemical
Reg. No./Substance:
0/6-(4-hydroxyphenyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone; 0/BRCA2 Protein; 0/BRCA2 protein, human; 0/DNA-Binding Proteins; 0/MRE11A protein, human; 0/Pyrimidinones; 0/Thiones; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases

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