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detect O
6
-meG DNA lesions and subsequently stimulate
MMR-c-Abl-GADD45
a
signaling that specifically medi-
ates G
2
cell cycle checkpoint arrest responses to presum-
ably repair mismatched DNA lesions before proceeding
through mitosis (see
Figure 9.4
). Detection of O
6
meG
lesions can also trigger a separate MMR-c-Abl-p73
a
signaling pathway that specifically mediates apoptosis,
eliminating severely damaged and highly mutagenic
cells (see
Figure 9.4
). In contrast, MMR-deficient cells
ignore these DNA lesions, leading to chemoresistance
and damage tolerance to O
6
-meG DNA lesions gener-
ated by specific alkylating agents, such as TMZ. The
net effect is the emergence of drug-resistant, highly
mutagenic cell populations that progress rapidly to kill
the patient. Potential strategies to overcome MMR-defi-
cient mediated chemoresistance based on accumulated
evidence were discussed and included the use of agents,
such as FdCyd, that can simultaneously hypomethylate
an epigenetically silenced hMLH1 promoter resulting in
hMLH1 re-expression, and sensitize the emerging cells
that have restored MMR capacity.
10. Lahue RS, Su SS, Modrich P. Requirement for d(GATC) sequences
in Escherichia coli mutHLS mismatch correction. Proc Natl Acad
Sci, USA 1987;
84
:1482
6.
11. Lahue RS, Au KG, Modrich P. DNA mismatch correction in
a defined system. Science 1989;
245
:160
e
4.
12. Grilley M, Welsh KM, Su SS, Modrich P. Isolation and charac-
terization of the Escherichia coli mutL gene product. J Biol Chem
1989;
264
:1000
e
4.
13. Cooper DL, Lahue RS, Modrich P. Methyl-directed mismatch
repair is bidirectional. J Biol Chem 1993;
268
:11823
e
9.
14. Berardini M, Mazurek A, Fishel R. The effect of O6-methyl-
guanine DNA adducts on the adenosine nucleotide switch
functions of hMSH2-hMSH6 and hMSH2-hMSH3. J Biol Chem
2000;
275
:27851
e
7.
15. Kolodner R. Biochemistry and genetics of eukaryotic mismatch
repair. Genes Dev 1996;
10
:1433
e
42.
16. Jiricny J. Replication errors: cha(lle)nging the genome. EMBO J
1998;
17
:6427
e
36.
17. Kolodner RD, Marsischky GT. Eukaryotic DNA mismatch repair.
Curr Opin Genet Dev 1999;
9
:89
e
96.
18. Buermeyer AB, Deschenes SM, Baker SM, Liskay RM. Mamma-
lian DNA mismatch repair. Annu Rev Genet 1999;
33
:533
e
64.
19. Fishel R, Kolodner RD. Identification of mismatch repair genes
and their role in the development of cancer. Curr Opin Genet Dev
1995;
5
:382
e
95.
20. Fishel R, Wilson T. MutS homologs in mammalian cells. Curr
Opin Genet Dev 1997;
7
:105
e
13.
21. Marti TM, Kunz C, Fleck O. DNA mismatch repair and mutation
avoidance pathways. J Cell Physiol 2002;
191
:28
e
Acknowledgments
The authors are grateful to Drs James K.V. Willson, Richard Fishel,
and Julio Morales for their helpful discussions. This work was sup-
ported by NIH/NCI grants R01 CA139217, R01 CA102792 and DOE
grant DE-FG02-09ER64789 to DAB. We also thank present and past
members of the Boothman laboratory for their helpful discussions of
our work on MMR signaling of G
2
cell cycle checkpoint and cell death
(apoptotic) responses. This is manuscript CSCN 061 for the Cell Stress
and Cancer Nanomedicine Program in the Simmons Comprehensive
Cancer Center.
41.
22. Glazer PM, Sarkar SN, Chisholm GE, Summers WC. DNA
mismatch repair detected in human cell extracts. Mol Cell Biol
1987;
7
:218
e
24.
23. Thomas DC, Roberts JD, Kunkel TA. Heteroduplex repair in
extracts of human HeLa cells. J Biol Chem 1991;
266
:3744
e
51.
24. Holmes Jr J, Clark S, Modrich P. Strand-specific mismatch
correction in nuclear extracts of human and Drosophila mela-
nogaster cell lines. Proc Natl Acad Sci, USA 1990;
87
:5837
e
41.
25. Genschel J, Modrich P. Mechanism of 5
0
-directed excision in
human mismatch repair. Mol Cell 2003;
12
:1077
e
86.
26. Zhang Y, Yuan F, Presnell SR, et al. Reconstitution of 5
0
-directed
human mismatch
e
References
repair
in
a
purified
system. Cell
1. Fishel R. Mismatch repair, molecular switches, and signal trans-
duction. Genes Dev 1998;
12
:2096
705.
27. Acharya S, Wilson T, Gradia S, et al. hMSH2 forms specific
mispair-binding complexes with hMSH3 and hMSH6. Proc Natl
Acad Sci, USA 1996;
93
:13629
2005;
122
:693
e
101.
2. Branch P, Hampson R, Karran P. DNA mismatch binding defects,
DNA damage tolerance, and mutator phenotypes in human
colorectal carcinoma cell lines. Cancer Res 1995;
55
:2304
e
34.
28. Palombo F, Iaccarino I, Nakajima E, Ikejima M, Shimada T,
Jiricny J. hMutSbeta, a heterodimer of hMSH2 and hMSH3, binds
to insertion/deletion loops in DNA. Curr Biol 1996;
6
:1181
e
9.
3. Modrich P, Lahue R. Mismatch repair in replication fidelity,
genetic recombination, and cancer biology. Annu Rev Biochem
1996;
65
:101
e
4.
29. Li GM, Modrich P. Restoration of mismatch repair to nuclear
extracts of H6 colorectal tumor cells by a heterodimer of human
MutL homologs. Proc Natl Acad Sci, USA 1995;
92
:1950
e
33.
4. Modrich P. Methyl-directed DNA mismatch correction. J Biol
Chem 1989;
264
:6597
e
600.
5. Modrich P. Strand-specific mismatch repair in mammalian cells. J
Biol Chem 1997;
272
:24727
e
4.
30. Raschle M, Marra G, Nystrom-Lahti M, Schar P, Jiricny J. Iden-
tification of hMutLbeta, a heterodimer of hMLH1 and hPMS1. J
Biol Chem 1999;
274
:32368
e
30.
6. Li LS, Morales JC, Veigl M, et al. DNA mismatch repair (MMR)-
dependent 5-fluorouracil cytotoxicity and the potential for new
therapeutic targets. Br J Pharmacol 2009;
158
:679
e
75.
31. Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonu-
cleolytic function of MutLalpha in human mismatch repair. Cell
2006;
126
:297
e
92.
7. Lu AL, Clark S, Modrich P. Methyl-directed repair of DNA base-
pair mismatches
e
308.
32. Reenan RA, Kolodner RD. Isolation and characterization of two
Saccharomyces cerevisiae genes encoding homologs of the
bacterial HexA and MutS mismatch repair proteins. Genetics
1992;
132
:963
e
in
vitro. Proc Natl Acad
Sci, USA
43.
8. Su SS, Modrich P. Escherichia coli mutS-encoded protein binds
to mismatched DNA base pairs. Proc Natl Acad Sci, USA
1986;
83
:5057
1983;
80
:4639
e
73.
33. Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene
homolog MSH2 and its association with hereditary nonpolyposis
colon cancer. Cell 1993;
75
:1027
61.
9. Welsh KM, Lu AL, Clark S, Modrich P. Isolation and character-
ization of the Escherichia coli mutH gene product. J Biol Chem
1987;
262
:15624
e
e
e
9.
e
38.
