Biology Reference
In-Depth Information
been elucidated. Most MMR knockout mice exhibit
mutator phenotypes (microsatellite instability, MSI)
and are cancer-prone (
Table 9.2
).
Loss of MMR by mutation of hMLH1 or hMSH2
genes is the major causative reason underlying heredi-
tary nonpolyposis colorectal cancer (HNPCC).
33,34,39
e
41
Epigenetic silencing of hMLH1 expression by promoter
hypermethylation is a major contributor to sporadic
colorectal, gastric, endometrial, and ovarian cancers
with MMR- deficient phenotypes.
77
e
86
Loss of MMR is accompanied by Microsatellite insta-
bility (MSI). Microsatellites are short, repetitive elements
in genomic DNA consisting of one to six bases per repeat
unit and are non-randomly distributed throughout the
human genome.
87,88
Failure to repair replication-
associated errors due to defective MMR allows tolerance
of small 1
influencing transcription rates, RNA stabilities, splicing
efficiencies, and RNA-protein interactions.
In addition to its role in post-replicative DNA repair,
MMR proteins are also integral to cellular responses to
exogenous DNA damage. Deficiencies in MMR function
result in “damage tolerance,” culminating in resistance to
a wide variety of commonly used therapeutic agents.
89
These include methylating agents (Temozolomide
(TMZ); procabazine; N-methyl-N'-nitro-N-nitrosoguani-
dine [MNNG]; N-methyl-N-nitrosourea [MNU]), antime-
tabolites (6-thioguanine [6-TG], mercaptopurine,
5-fluoropyrimidines), and bifunctional alkylating
agents (e.g., platinum compounds: cisplatin and
carboplatin).
90
e
98
Loss of MMR also confers additional
tolerance to cellular redox reactions within the cell,
such as those occurring after oxidizing agents (e.g., dox-
yrubicin) or ionizing radiation (IR).
99,100
Such tolerance
represents a formidable challenge to therapy, since simul-
taneous increases in mutagenesis and drug resistance
ultimately result in advanced progression of cancer.
Responses to 5-FU bear this out, where colorectal cancer
patients with MMR deficiencies (MSI/MIN) respond
more poorly and have worse outcomes than patients
with intact MMR, but have chromosomal
3 DNA base loops that remain unmatched
throughout the genome, but especially in regions of
repetitive microsatellite DNA, giving rise to MSI regions
in which large variations in DNA lengths are visible after
amplification of the MSI DNA regions via polymerase
chain reactions. Microsatellites are located in intragenic
regions (promoters, 3
0
-untranslated regions, and introns)
and can be important regulators of gene expression by
e
instability
TABLE 9.2 Phenotypes of MMR-Deficient Mice
Gene
MSI
Tumor
References
De Wind et al. (1995)
62
Reitmair et al. (1995)
63
Smits et al. (2000)
64
MSH2
Yes
Lymphoma, GI, skin, and
other tumors
Lin et al. (2004)
65
MSH2 G674A/G674A
Yes
Lymphoma, GI, skin
De Wind et al. (1999)
66
Edelmann et al. (2000)
67
MSH3
Yes
Tumor free or GI tumors
at a very late age
Edelmann et al. (1997)
68
De Wind et al. (1999)
66
Edelmann et al. (2000)
67
MSH6
Low MSI in dinucleotide
repeats
Lymphoma, GI, skin, and
other tumors
Yang et al. (2004)
69
Yang et al. (2004)
70
MSH6 T1217D/T1217D
Yes
Lymphoma, GI, skin
Edelmann et al. (2000)
67
De Wind et al. (1999)
66
MSH3-/- / MSH6-/-
Yes
Lymphoma, GI, skin, and
other tumors
Baker et al. (1996)
71
Edelmann et al. (1996)
72
Prolla et al. (1998)
73
Edelmann et al. (1999)
74
MLH1
Yes
Lymphoma, GI, skin, and
other tumors
Prolla et al. (1998)
73
PMS1
Low MSI in mononucleotide
repeats and dinucleotide
None
Prolla et al. (1998)
73
Baker et al. (1995)
75
PMS2
Yes
Lymphoma and sarcoma
Lipkin et al. (2002)
44
MLH3
Low MSI in mononucleotide
repeats and dinucleotide
Not available
Wei et al. (2003)
76
ExoI
Yes
Lymphoma
