"Endonucleolytic function of MutLalpha in human mismatch repair."
Kadyrov FA, Dzantiev L, Constantin N, Modrich P
Half of hereditary nonpolyposis colon cancer kindreds harbor mutations
that inactivate MutLalpha (MLH1*PMS2 heterodimer). MutLalpha is required
for mismatch repair, but its function in this process is unclear. We show
that human MutLalpha is a latent endonuclease that is activated in a
mismatch-, MutSalpha-, RFC-, PCNA-, and ATP-dependent manner. Incision of
a nicked mismatch-containing DNA heteroduplex by this four-protein system
is strongly biased to the nicked strand. A mismatch-containing DNA segment
spanned by two strand breaks is removed by the 5'-to-3' activity of
MutSalpha-activated exonuclease I. The probable endonuclease active site
has been localized to a PMS2 DQHA(X)(2)E(X)(4)E motif. This motif is
conserved in eukaryotic PMS2 homologs and in MutL proteins from a number
of bacterial species but is lacking in MutL proteins from bacteria that
rely on d(GATC) methylation for strand discrimination in mismatch repair.
Therefore, the mode of excision initiation may differ in these organisms.
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Last modification of this entry: Dec. 10, 2009
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