Biology Reference
In-Depth Information
MutS
b
MutS
a
PCNA
MutS
MutS
MutS
a
b
b
PCNA
?
?
MutH
MutL
MutL
MutL
a
g
-Proteobacteria
Other prokaryotes
Eukaryotes
F
IG
. 1. Mechanisms of mismatch recognition and strand discrimination. In bacteria, homo-
dimeric MutS recognizes mismatches or small insertion/deletion loops (indels) assisted by the
b
subunit of polymerase III. In an ATP-dependent manner, MutS recruits MutL to the complex.
In eukaryotes, heterodimeric MutS
a
is primarily responsible for correcting mismatches or small
indels assisted by PCNA, the processivity subunit of polymerase
d
. Similarly, MutS
a
recruits
MutL
a
to this complex in an ATP-dependent manner. In
g
-proteobacteria (left), formation of the
MutS-MutL-heteroduplex complex activates the endonuclease activity of MutH that selectively
nicks the newly synthesized strand. However, most prokaryotes (center) and all eukaryotes (right)
lack a
mutH
gene. MutL homologs from these organisms encompass a conserved endonuclease
motif (depicted as a red dot) that selectively cuts the nicked strand of the DNA. However, the origin
of the primary nick remains unclear.
conformational change allows the MutS
ATP complex to become a sliding
clamp.
22,25-27
This conformational change favors the recruitment of additional
mismatch repair factors to the site of damage and, in turn, signals repair.
MutL is one of the factors recruited to mismatches in a MutS- and ATP-
dependent manner (
Fig. 1
).
28
MutL is a dimeric, weak ATPase from the GHL
(Gyrase B-Hsp90-MutL) family of ATPases.
29,30
As its primary role is to
mediate the protein-protein interactions during mismatch recognition and
strand removal, MutL has been historically classified as a molecular match-
maker.
31
Formation of a ternary complex between MutS, MutL, and mis-
matched DNA (MutS-MutL-heteroduplex) is sufficient to activate the latent
endonuclease MutH.
MutH is a member of the type II family of restriction endonucleases that
nicks the unmethylated strand of hemimethylated guanine, adenine, thymine,
cytosine (GATC) sequences.
32,33
In
E. coli
, all adenines within GATC sequences
are methylated by dam methylase; however, after the passage of the replication
