Biology Reference
In-Depth Information
CHAPTER
2
MGMT: A Critical DNA Repair Gene Target
for Chemotherapy Resistance and for Stem Cell
Protection
Lili Liu, Yuan Lin, Stanton L. Gerson
Case Western Reserve University, Cleveland, OH
very low levels.
5
The lowest activity appears in the
bone marrow CD34 cells
6
and the pancreas.
7
Of interest,
stromal cells of the bone marrow contain much higher
MGMT activity than hematopoietic stem and progenitor
cells. Within normal tissues, a small proportion of cells
may lack MGMT activity, and this may be influenced
by a specific polymorphism, the T allele of the
rs16906252 single nucleotide polymorphism (SNP).
8
In
addition, in children, some regions of the brain, may
not express MGMT.
9
A number of studies have found
that loss of expression may be associated with tumor
transformation, mutations in
p53
or
K-ras
or tumor devel-
opment and progression. Clinically, for individuals with
a tumor receiving alkylating therapy, low levels of
MGMT in normal tissues may be associated with neuro-
toxicity. Furthermore, in animal studies, low MGMT
activity predisposes to methylating agent-induced
malignancies, particularly lymphomas, breast cancer in
the rat, lung cancers, and colon cancers. Inmurine carcin-
ogen induction studies, high levels of MGMT are protec-
tive,
10,11
and tissues do not develop O
6
-methylguanine-
induced G to A mutations in
K-ras
. This indicates that
a single type of DNA base methylation is carcinogenic
and that removal of this particular O
6
meG lesion will
prevent tumor induction, the first evidence that MGMT
acts as a tumor suppressor. From this observation, it is
possible to extrapolate that in human tissues, low
MGMT may increase susceptibility to environmental
carcinogenesis, particularly agents that induce alkylation
at the O
6
of guanine. For instance, the low MGMT in
human CD34 cells might predispose to alkylating
agent-associated “secondary” leukemia.
12,13
While all types of human tumors express MGMT,
expression in specific tumors and cell lines may be
DNA in the living cell is subjected to endogenous and
exogenous damage. All organisms have developed
a complex network of DNA repair mechanisms that
mediate a variety of different DNA repair pathways to
remove and repair these lesions, including: direct
reversal, base excision repair, nucleotide excision repair,
mismatch repair, and DNA double-strand break repair
pathways. The direct reversal repair is specific to the
types of damage that can be repaired without involving
breakage of the DNA backbone and resynthesis of DNA.
The protein MGMT (O
6
-methylguanine-DNA methyl-
transferase), also known as AGT (O
6
-alkylguanine trans-
ferase), is well known to play a significant role in the
direct reversal of DNA damage, O
6
-alkylguanine, by
a dealkylation reaction.
MGMT EXPRESSION IN NORMAL AND
TUMOR TISSUES
MGMT is a conserved protein from prokaryotes
through eukaryotes. In humans, MGMT is ubiquitously
expressed although levels vary and promoter methyla-
tion can shut off the gene (see below). The key regulators
of MGMT gene expression remain ill defined. There are
a number of regulatory elements in the MGMT promoter,
and a number of stimuli may increase MGMT expres-
sion, such as irradiation, glucocorticoid exposure, and
cAMP.
1
There is no clear relationship between these
factors and physiologic expression of MGMT in most
normal cells and tissues. In a number of species, liver
contains the highest level of MGMT, followed by lung
and kidney.
2
e
4
Brain has much more heterogeneous
expression, with some normal brain samples having
