Biology Reference
In-Depth Information
members.
31
The minimal 5
0
/
5
0
excision reac-
tion requires hMSH2-hMSH6 (or hMSH2-hMSH3),
hMLH1-hPMS2, Exo I, RPA, PCNA, and RFC.
31
Re-
synthesis of the single-stranded gap requires DNA Poly-
merase
d
, and DNA ligase I, and may be modestly
enhanced by HMGB1 activity.
26
The detailed functions
of these human MMR proteins have been summarized
in
Table 9.1
.
3
0
and 3
0
/
DNA) are recognized by the hMSH2-hMSH6 hetero-
dimer, while insertion/deletion loop-type mismatched
DNA lesions are recognized by the hMSH2-hMSH3 het-
erodimer.
27,28
Human homologs of MutL form hMLH1-
hPMS2 and/or hMLH1-hMLH3 heterodimers and
function downstream of hMutS recognition
complexes.
29,30
Importantly, the mismatched DNA
substrate must contain a pre-introduced single-stranded
scission (i.e., nick), either at the 5
0
-or3
0
- end of the DNA
mismatch lesion. Nuclease activity required for DNA
patch excision appears to be accomplished by a combina-
tion of a 5
0
-exonuclease (Exo I) and an intrinsic ssDNA
endonuclease activity found in some MLH family
MMR Status and Cancer
Mouse knockout models have been developed for
each of the MMR genes, and their phenotypes have
TABLE 9.1 MMR Components and Their Functions
E. coli
Human
Function
References
Reenan et al. (1992)
32
Fishel et al. (1993)
33
Leach et al. (1993)
34
Palombo et al. (1995)
35
Drummond et al. (1995)
36
hMutS
a
(MSH2-MSH6)
MutS
DNA mismatch recognition
Habraken et al. (1996)
37
Wilson et al. (1999)
38
hMutS
b
(MSH2-MSH3)
Bronner et al. (1994)
39
Li et al. (1995)
29
Nicolaides et al. (1994)
40
Papadopoulos et al. (1994)
41
MutL
hMutL
a
(MLH1-PMS2)
Molecular matchmaker;
endonuclease;
termination of mismatch-provoked excision
Prolla et al. (1994)
42
hMutL
b
(MLH1-PMS1)
Function of human heterodimer unknown
Svetlanov et al. (2004)
43
Lipkin et al. (2002)
44
Harfe et al. (2000)
45
Flores-Rozas et al. (1998)
46
Harfe et al. (2000)
47
Lipkin et al. (2000)
48
hMutL
g
(MLH1-MLH3)
Meiotic recombination; suppresses
some insertion
deletion mismatch
e
mutagenesis
Li et al. (2008)
49
Kunkel et al. (2005)
50
MutH
None
Strand discrimination
Li et al. (2008)
49
UvrD
None
DNA helicase
Schmutte et al. (1998)
51
Tishkoff et al. (1998)
52
Tishkoff et al. (1997)
53
ExoI,
ExoVII,
ExoX,
RecJ
ExoI
Excision of ssDNA, dsDNA
Longley et al. (1997)
54
DNA pol III
Pol
d
DNA re-synthesis
Gu et al. (1998)
55
Johnson et al. (1996)
56
Umar et al. (1996)
57
b
-clamp
PCNA
Initiation of MMR,
DNA re-synthesis
Ramilo et al. (2002)
58
Lin et al. (1998)
59
SSB
RPA
Participates in excision and DNA synthesis
Yuan et al. (2004)
60
Dzantiev et al. (2004)
61
HMGB1
Mismatch-provoked excision
PCNA loading; 3
0
nick-directed repair;
activation of MutL
a
endonuclease
Kadyrov et al. (2006)
31
RFC
Zhang et al. (2005)
26
DNA ligase
DNA ligase I
Nick ligation
