T

3'OH

FI c u tt E 9-6 Directionality in mismatch repair: exo nuclease removal of mismatched dna.

(a) Unmethylated GATC is 5' of mutation (b) Unmethylated CATC is 3' of mutation

Even though eukaryotic cells have mismatch repair systems, they lack MutH and E. coli's clever trick of using hemimethylation to tag the parental strand. (Indeed, most bacteria lack Dam methylase and ere also unable to use hemimethylation to mark the newly synthesized strand.) How then does the mismatch repair system know which of the two strands to correct? Lagging strand synthesis, as we saw in Chapter 8, takes place discontinuously with the formation of Okazaki fragments that are joined to previously synthesized DNA by DNA ligase. Prior to the ligation step, the Okazaki fragment is separated from previously synthesized DNA by a nick, which can be thought of as being equivalent to the nick created in E. co!i by MutH on the newly synthesized strand, indeed, extracts of eukaryotic cells will repair mismatches in artificial templates that contain a nick and do so selectively on the strand that carries the nick, Recent results indicate that human homologs of MutS (MSI I) interact with the sliding clamp component of the replisome (PCNA, which we discussed in Chapter fi), and would thereby be recruited to the site of discontinous DNA synthesis on the lagging strand, interaction with the sliding clamp could also recruit mismatch repair proteins to the 3' (growing) end of die leading strand.

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