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Vol. 15, No. 6, pp. 724-736, March 15, 2001
Institute of Medical Radiobiology of the University of Zürich and
the Paul Scherrer Institute, CH-8008 Zürich, Switzerland.
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 hMutS
and
hMutS
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 hMutS, 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.
[Key Words: PCNA; hMSH6; hMSH3; mismatch repair; DNA repair; replication foci]
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