Document Detail


Human MutL-complexes monitor homologous recombination independently of mismatch repair.
MedLine Citation:
PMID:  19022408     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The role of mismatch repair proteins has been well studied in the context of DNA repair following DNA polymerase errors. Particularly in yeast, MSH2 and MSH6 have also been implicated in the regulation of genetic recombination, whereas MutL homologs appeared to be less important. So far, little is known about the role of the human MutL homolog hMLH1 in recombination, but recently described molecular interactions suggest an involvement. To identify activities of hMLH1 in this process, we applied an EGFP-based assay for the analysis of different mechanisms of DNA repair, initiated by a targeted double-stranded DNA break. We analysed 12 human cellular systems, differing in the hMLH1 and concomitantly in the hPMS1 and hPMS2 status via inducible protein expression, genetic reconstitution, or RNA interference. We demonstrate that hMLH1 and its complex partners hPMS1 and hPMS2 downregulate conservative homologous recombination (HR), particularly when involving DNA sequences with only short stretches of uninterrupted homology. Unexpectedly, hMSH2 is dispensable for this effect. Moreover, the damage-signaling kinase ATM and its substrates BLM and BACH1 are not strictly required, but the combined effect of ATM/ATR-signaling components may mediate the anti-recombinogenic effect. Our data indicate a protective role of hMutL-complexes in a process which may lead to detrimental genome rearrangements, in a manner which does not depend on mismatch repair.
Authors:
Simone Yasmin Siehler; Michael Schrauder; Ulrike Gerischer; Sharon Cantor; Giancarlo Marra; Lisa Wiesmüller
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-29
Journal Detail:
Title:  DNA repair     Volume:  8     ISSN:  1568-7864     ISO Abbreviation:  DNA Repair (Amst.)     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-01-12     Completed Date:  2009-04-07     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  101139138     Medline TA:  DNA Repair (Amst)     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  242-52     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / metabolism*
Adenosine Triphosphatases / metabolism
Ataxia Telangiectasia Mutated Proteins
Basic-Leucine Zipper Transcription Factors / metabolism
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Chromosomes, Human / metabolism
DNA Breaks, Double-Stranded
DNA Mismatch Repair*
DNA Repair Enzymes / metabolism
DNA-Binding Proteins / metabolism
Fanconi Anemia Complementation Group Proteins / metabolism
Humans
Multiprotein Complexes / metabolism*
MutS Homolog 2 Protein / metabolism
Neoplasm Proteins / metabolism
Nuclear Proteins / metabolism*
Protein-Serine-Threonine Kinases / metabolism
RecQ Helicases / metabolism
Recombination, Genetic*
Tumor Suppressor Proteins / metabolism
Grant Support
ID/Acronym/Agency:
R01 CA129514/CA/NCI NIH HHS; R01 CA129514-04/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/BACH1 protein, human; 0/Basic-Leucine Zipper Transcription Factors; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Fanconi Anemia Complementation Group Proteins; 0/MLH1 protein, human; 0/Multiprotein Complexes; 0/Neoplasm Proteins; 0/Nuclear Proteins; 0/PMS1 protein, human; 0/Tumor Suppressor Proteins; EC 2.7.11.1/ATM protein, human; EC 2.7.11.1/Ataxia Telangiectasia Mutated Proteins; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/Bloom syndrome protein; EC 3.6.1.-/PMS2 protein, human; EC 3.6.1.3/MSH2 protein, human; EC 3.6.1.3/MutS Homolog 2 Protein; EC 3.6.4.12/RecQ Helicases; EC 6.5.1.-/DNA Repair Enzymes
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