Biology Reference
In-Depth Information
The Functions of MutL in
Mismatch Repair: The Power
of Multitasking
Alba Guarn ´
Department of Biochemistry and
Biomedical Sciences, McMaster University,
Hamilton, Ontario, Canada
I. Overview of DNA Mismatch Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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A. DNA Mismatch Repair in
Escherichia coli
........................................
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B. Strand Discrimination in Mismatch Repair in Organisms Lacking MutH .
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C. The Multiple Faces of MutL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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II. MutL is a Multidomain Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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A. The ATPase Domain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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B. DNA Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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C. The Dimerization Domain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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III. Architecture of the Endonuclease Domain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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A. The Endonuclease Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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B. MutL is an Mn
2
þ
-Dependent Endonuclease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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C. The Regulatory Zn
2
þ
-Binding Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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D. The Endonuclease Activity of MutL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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IV. Regulation of the Endonuclease Activity of MutL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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A. DNA Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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B. Stimulatory Effect of the Processivity Clamp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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C. Mismatch Dependency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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V. Concluding Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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DNA mismatch repair enhances genomic stability by correcting errors that
have escaped polymerase proofreading. One of the critical steps in DNA
mismatch repair is discriminating the new from the parental DNA strand as
only the former needs repair. In
Escherichia coli
, the latent endonuclease
MutH carries out this function. However, most prokaryotes and all eukaryotes
lack a
mutH
gene. MutL is a key component of this system that mediates
protein-protein interactions during mismatch recognition, strand discrimina-
tion, and strand removal. Hence, it had long been thought that the primary
function of MutL was coordinating sequential mismatch repair steps. However,
recent studies have revealed that most MutL homologs from organisms lacking
MutH encode a conserved metal-binding motif associated with a weak endo-
nuclease activity. As MutL homologs bearing this activity are found only in
organisms relying on MutH-independent DNA mismatch repair, this finding
unveils yet another crucial function of the MutL protein at the strand discrim-
ination step. In this chapter, we review recent functional and structural work
