DNA mismatch repair
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Figure: Crystal structure of MutS(beta) bound to DNA.
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Wei Yang group (The National Institutes of Health)
Wei Yang's group at the NIH advanced research in the fight
against cancer by providing key insights on mismatch recognition by
MutS(beta). Mismatched base pairs resulting from misincorporation during
replication lead to mutations and genomic instability if not repaired. In
humans, inactivation of the MutS or MutL proteins, essential for mismatch
repair, causes a condition known as Lynch Syndrome that leads to a
predisposition for hereditary colorectal and other cancers. MutS(alpha), one
of two MutS heterodimers in eukaryotes, is highly similar to bacterial MutS
and recognizes a base mispair or 1-2 unpaired bases. In contrast,
MutS(beta), a heterodimer of Msh2 and Msh3, recognizes insertion-deletion
loops (IDL) of 2-15 nucleotides, as well as DNA with a 3' single-stranded
overhang. Crystals of human MutS(beta) were fragile and highly radiation
sensitive. The Yang group determined four structures of MutS(beta) bound to
different IDL loops. MutS(beta) bends the substrate DNA much more than does
MutS(alpha) and displaces the unpaired bases into the major groove rather
than the minor groove as does MutS(alpha). Furthermore, the structures of
MutS(beta) reveal the asymmetry between its two homologous subunits and
suggest a mechanism for asymmetric modulation of ATP binding and hydrolysis
by a mismatched DNA substrate. Thus association of MutS(beta) with a
mismatch DNA can recruit other repair factors and signal for repair
initiation.
Citation:
Gupta, S, Gellert, M, Yang, W. Mechanism of mismatch recognition revealed by
human MutS(beta) bound to unpaired DNA loops, Nat Struct Mol Biol 19, 72-78
(2012).
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