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BRCA1 is required for hMLH1 stabilization following doxorubicin-induced DNA damage.
MedLine Citation:
PMID:  21864706     Owner:  NLM     Status:  Publisher    
Human DNA mismatch repair (MMR) is involved in the removal of DNA base mismatches that arise either during DNA replication or are caused by DNA damage. In this study, we show that the activation of the MMR component hMLH1 in response to doxorubicin (DOX) treatment requires the presence of BRCA1 and that this phenomenon is mediated by an ATM/ATR dependent phosphorylation of the hMLH1 Ser-406 residue. BRCA1 is an oncosuppressor protein with a central role in the DNA damage response and it is a critical component of the ATM/ATR mediated checkpoint signaling. Starting from a previous finding in which we demonstrated that hMLH1 is able to bind to BRCA1, in this study we asked whether BRCA1 might be the bridge for ATM/ATR dependent phosphorylation of the hMLH1 molecular partner. We found that: (i) the negative modulation of BRCA1 expression is able to produce a remarkable reversal of hMLH1 stabilization, (ii) BRCA1 is required for post-translational modification produced by DOX treatment on hMLH1 which is, in turn, attributed to the ATM/ATR activity, (iii) the serine 406 phosphorylatable residue is critical for hMLH1 activation by ATM/ATR via BRCA1. Taken together, our data lend support to the hypothesis suggesting an important role of this oncosuppressor as a scaffold or bridging protein in DNA-damage response signaling via downstream phosphorylation of the ATM/ATR substrate hMLH1.
Francesco Romeo; Lucia Falbo; Maddalena Di Sanzo; Roberta Misaggi; Maria C Faniello; Giuseppe Viglietto; Giovanni Cuda; Francesco Costanzo; Barbara Quaresima
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-8-16
Journal Detail:
Title:  The international journal of biochemistry & cell biology     Volume:  -     ISSN:  1878-5875     ISO Abbreviation:  -     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-8-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9508482     Medline TA:  Int J Biochem Cell Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Ltd.
Department of Experimental and Clinical Medicine, "Magna Græcia" University of Catanzaro, "Salvatore Venuta" Campus, Viale Europa, 88100 Catanzaro, Italy.
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