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The common mismatch repair (MMR) system processed by MutS/MutL and their homologs
was identified in Bacteria and Eukarya. However no evidence of a functional MutS/L homolog
has been reported for archaeal organisms, and it has not been known whether MMR is conserved
in Archaea. We discovered an endonuclease that cleaves double-stranded DNA containing a
mismatched base pair from Pyrococcus furiosus, and named it as Endonuclease MS (EndoMS)
as the mismatch-specific endonuclease. The EndoMS homolog from Thermococcus kodakarensis
clearly cleaved both strands of double-stranded DNA into 5'-protruding forms, with the mismatched
base pair in the central position. The discovery of this endonuclease suggests the existence of
a novel MMR process, initiated by the double-strand break generated by the EndoMS, in Archaea
and some Bacteria. The complex structure of EndoMS with double-stranded DNA unexpectedly
revealed that the mismatched bases were flipped out into binding sites, and the overall architecture
most resembled that of restriction enzymes. The structure of apo form indicated that movement
of the C-terminal domain from resting state was required for activity. Involvement of this endonuclease
for a mismatch repair pathway, different from the MutS/L system will be discussed.