hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci

Proliferating cell nuclear antigen (PCNA) has been implicated in eukaryotic postreplicative mismatch correction, but the nature of its interaction with the repair machinery remained enigmatic. We now show that PCNA binds to the human mismatch binding factors hMutSalpha and hMutSbeta via their hMSH6...

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Bibliographic Details
Published in:Genes & development 2001-03, Vol.15 (6), p.724-736
Main Authors: Kleczkowska, H E, Marra, G, Lettieri, T, Jiricny, J
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Amino Acid Sequence
Animals
Base Pair Mismatch
Blotting, Western
Cell Line
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - metabolism
DNA - metabolism
DNA Repair
DNA Replication
DNA-Binding Proteins - metabolism
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Fluorescent Antibody Technique, Indirect
Genetic Complementation Test
HeLa Cells
hMSH3 protein
hMSH6 protein
Humans
Microscopy, Fluorescence
mismatch repair
Molecular Sequence Data
Multidrug Resistance-Associated Proteins
Mutation
MutS Homolog 3 Protein
Peptides - chemistry
Precipitin Tests
Proliferating Cell Nuclear Antigen - metabolism
Protein Binding
Protein Structure, Tertiary
Recombinant Proteins - metabolism
Research Paper
Transfection
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Summary:Proliferating cell nuclear antigen (PCNA) has been implicated in eukaryotic postreplicative mismatch correction, but the nature of its interaction with the repair machinery remained enigmatic. We now show that PCNA binds to the human mismatch binding factors hMutSalpha and hMutSbeta via their hMSH6 and hMSH3 subunits, respectively. The N-terminal domains of both proteins contain the highly conserved PCNA-binding motif Qxx[LI]xx[FF]. A variant of hMutSalpha, lacking this motif because of deletion of 77 N-terminal residues of the hMSH6 subunit, no longer was able to interact with PCNA in vitro and failed to restore mismatch repair in hMSH6-deficient cells. Colocalization of PCNA and hMSH6 or hMSH3 to replication foci implies an intimate link between replication and mismatch correction. We postulate that PCNA plays a role in repair initiation by guiding the mismatch repair proteins to free termini in the newly replicated DNA strands.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.191201