MED1, a Novel Human methyl-CpG-binding Endonuclease, Interacts with DNA Mismatch Repair Protein MLH1

The DNA mismatch repair (MMR) is a specialized system, highly conserved throughout evolution, involved in the maintenance of genomic integrity. To identify novel human genes that may function in MMR, we employed the yeast interaction trap. Using the MMR protein MLH1 as bait, we cloned MED1. The MED1...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (7), p.3969-3974
Main Authors: Bellacosa, Alfonso, Cicchillitti, Lucia, Schepis, Filippo, Riccio, Antonio, Yeung, Anthony T., Matsumoto, Yoshihiro, Golemis, Erica A., Genuard, Maurizio, Neri, Giovanni
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Amino Acid Sequence
Base Pair Mismatch
Base Sequence
Biological Sciences
Carrier Proteins
Cell Line
Cell lines
Cloning, Molecular
Cultured cells
Deoxyribonucleic acid
DNA
DNA Repair
Endodeoxyribonucleases - chemistry
Endodeoxyribonucleases - isolation & purification
Endodeoxyribonucleases - metabolism
Genetic screening
Humans
Kinetics
Microsatellite Repeats
Molecular Sequence Data
Mutation
MutL Protein Homolog 1
Neoplasm Proteins - isolation & purification
Neoplasm Proteins - metabolism
Nuclear Proteins
Oligodeoxyribonucleotides
Oligonucleotides
Plasmids
Proteins
Recombinant Fusion Proteins - biosynthesis
Recombinant Proteins - isolation & purification
Recombinant Proteins - metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Social interaction
Transfection
Yeast
Yeasts
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Summary:The DNA mismatch repair (MMR) is a specialized system, highly conserved throughout evolution, involved in the maintenance of genomic integrity. To identify novel human genes that may function in MMR, we employed the yeast interaction trap. Using the MMR protein MLH1 as bait, we cloned MED1. The MED1 protein forms a complex with MLH1, binds to methyl-CpG-containing DNA, has homology to bacterial DNA repair glycosylases/lyases, and displays endonuclease activity. Transfection of a MED1 mutant lacking the methyl-CpG-binding domain (MBD) is associated with microsatellite instability (MSI). These findings suggest that MED1 is a novel human DNA repair protein that may be involved in MMR and, as such, may be a candidate eukaryotic homologue of the bacterial MMR endonuclease, MutH. In addition, these results suggest that cytosine methylation may play a role in human DNA repair.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.7.3969