Biology Reference
In-Depth Information
aimed at characterizing the multiple functions of MutL and discuss how the
endonuclease activity of MutL is regulated by other repair factors.
I. Overview of DNA Mismatch Repair
DNA mismatch repair corrects errors that have escaped the proofreading
activity of replicative polymerases, in turn increasing replication fidelity by two
to three orders of magnitude (reviewed in Refs.
1-4
). Defects in the mismatch
repair genes cause increased mutation rates and genetic instability,
5
the hall-
mark of Lynch syndrome. Families with Lynch syndrome, commonly known as
human non-polyposis colorectal cancer, have an increased risk of cancers of the
colon, stomach, small intestine, liver, gallbladder ducts, upper urinary tract,
brain, skin, and prostate—women with this disorder also have a high risk of
cancer of the endometrium and ovaries.
6,7
Beyond correcting replication errors, DNA mismatch repair proteins
recognize a variety of DNA lesions and coordinate transcription-coupled nu-
cleotide excision repair, meiotic recombination, cell cycle checkpoint control,
and apoptosis.
8,9
Recognition of alkylation lesions and intrastrand cross-links by
mismatch repair proteins results in cell cycle arrest and apoptosis when damage
is too extensive. In turn, mismatch repair-deficient tumor cells are highly
resistant to treatment with alkylating agents due to their inability to induce
apoptosis.
10,11
Underscoring the importance of these additional functions,
about a fourth of all sporadic cancers have associated mismatch repair defects.
9
These roles of the mismatch repair proteins are not considered further here,
but the reader is directed to excellent reviews on the topic.
2,4,12-14
A. DNA Mismatch Repair in
Escherichia coli
The components of the mismatch repair system were originally identified
and characterized in
Escherichia
coli.
15
In this paradigmatic system, three
proteins—MutS, MutL, and MutH—are required to recognize and initiate the
mismatch repair response (
Tabl e I
and
Fig. 1
).
MutS is a dimeric ATPase from the ABC (adenosine triphosphate (
A
TP)-
b
inding
c
assette) superfamily.
16
It recognizes single base-base mismatches and
insertion/deletion loops (indels) containing up to 4 unpaired bases with 10- to
1500-fold higher affinity than perfectly matched DNA.
17-20
The DNA- and
ATP-binding domains of MutS reside in opposite ends of the polypeptide
chain; however, the two regions are connected by a long transmitter helix
that mediates the nucleotide-dependent proofreading of the mismatch.
21-24
MutS is normally bound to adenosine diphosphate (ADP), but nucleotide-
exchange is favored once a mismatch is encountered and a concomitant
