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The Relationships Between Cancer, Chemotherapy, and DNA Repair
Shelly Beard, Fred Caton, Sarah Ivan, Edra London, and Katie Nelson
Biochemistry 465, Univ. of Maryland, College Park, MD 20742
INTRODUCTION:
According to the American Cancer Society, 45.67% of males and
38.09% of females developed invasive cancers from 2000-2002. In
addition, it is estimated that there will be over 550,000 deaths
attributed to cancer in 2006 in the United States. Prevention and
treatment of these cancers is a hot topic. Manipulation of DNA damage
and repair mechanisms is the basis for several treatment options.
DNA damage can occur naturally and there are countless enzymes
and pathways that serve to repair this damage in order to prevent any
lasting effects. While some base insertions, deletions, or point
mutations may be harmless due to redundancy and conservation of the
genetic code, other mutations can cause cells to become cancerous.
However, DNA damage can also be used to treat cancer by causing
enough DNA damage to lead to the death of the tumor cell. DNA repair
pathways include: nucleotide excision repair, base excision repair, nonhomologous end-joining, mismatch repair, homologous recombination
among others. This poster concentrates on the last two, providing
specific examples of how mismatch repair and homologous
recombination are related to cancer treatment.
Cancer treatment involving radiation and/or chemotherapy is an
interesting dichotomy because the ability of these agents to reduce
cancerous cells is related to their ability to cause DNA damage, while
these cells also have the ability to invoke pathways to repair this
damage (Madhusudan and Hickson, 2005). If one can inhibit DNA repair
in specific tumor cells, increased efficacy of the treatment can be
achieved.
Mismatch Repair
O6-Methylguanine DNA Methyltransferase (MGMT)
Homologous recombination (HR) plays an integral role in the
survival of tumor cells after radio- and chemotherapies. MDC1 is a
protein that senses DNA damage and aids in the transport of other
repair proteins to the site of damage. As shown in figure 4,
deficiency in MDC1 is similar to BRCA1, which is a known tumor
suppressing gene that aids in repairing DNA damage.
Programmed DNA
methylation plays an
important role in the
maintenance of normal gene
expression and genome
stability.
O6-methylguanine DNA
methyltransferase (MGMT) is
the gene that encodes O6alkylguanine DNA alkyltransferase (AGT), a DNA
repair protein that removes
abnormal alkyl adducts from
the O6 position of guanine
and less often, thymine (Fig.
2a). MGMT protects DNA from
mutagenic legions by
transferring the alkyl adduct
from the guanine to the
active site of MGMT (Cys145),
thereby inactivating the
enzyme so that one MGMT
molecule protects against one
DNA lesion prior to its
degradation.
Downstream Effects of MDC1 Disruption
• Homology-mediated repair
is impaired
• Increased sensitivity to
cross-linking agents and
ionizing radiation
• Decreased stability and
mobilization of key repair
protein Rad51
Therapeutic Strategies
Involving MDC1 Knockdown
Figure 2. AGT repair process: a. covalent transfer
of alkyl group; b. repair, G→A transition mutation,
or stand break can result. (Gerson et al., 2004).
MGMT’s Role in the Etiology of Cancer
• AGT protects healthy cells against exogenous carcinogenic damage.
• MGMT-promoter methylation shuts off MGMT expression which causes
DNA hypermethylation, and in turn, can silence other genes including
protective tumor suppressor genes such as p53.
MGMT and It’s Potential Applications in the Treatment of Cancer
Figure 1. Figure showing mismatch repair mechanism involving
key enzymes. (Iyer et al., 2006)
Cancer Relation To Mismatch Repair
•
Inactivation of mismatch repair causes hereditary nonpolyposis
colon cancer (HNPCC).
•
Mismatch repair deficiency also linked to development of certain
sporadic tumours in various tissues.
•
Mismatch repair may function as a general sensor of DNA
damage.
•
6-TG, FdU and cisplatin are used as antitumor drugs.
•
o
All are cytotoxic with intrinsic mutagenic
activity.
o
Defects in mismatch repair lead to a resistance
to these drugs.
o
Patients with mismatch repair deficient cancers
do not respond well to these drugs.
MutSa or MutLa (deficiency of the mismatch repair enzymes)
increases the rate of gene duplication 50-100 fold, which can
lead to cancer predisposition.
MGMT overexpression has been shown to prevent specific thymus, lung,
liver, skin, and intestine cancers induced by methylating agents in a mouse
model. (Gerson, 2004)
• MGMT hypermethlyation has
a potential role in pharmacoepigenomics as methylated
tumors are more sensitive to
the destructive effects of
alkylating drug therapies.
• AGT inhibitors can increase
the sensitivity of tumors to
alkylating agents, thereby
increasing the effectiveness of
such chemotherapeutic
treatment.
• MGMT is a target gene for the
protection of hematopoietic
stem cells during
chemotherapy for cancer. Stem
cells are protected from the
toxic affects of methylating
agents by MGMT expression.
Role of MDC1 in Homologous Recombination
Figure 4. MDC1 and BRCA1 deficient cells
show similar reductions in homologous
recombination. (Zhang et al., 2005)
• siRNA is the treatment of choice in silencing the gene that encodes
MDC1.
• Ionizing Radiation can be coupled with a pharmacological treatment to finish off cells that have compromised repair mechanisms.
• Chemotherapeutic agents such as mitomycin C become especially
effective against hypersensitive cells.
CONCLUSIONS:
DNA repair mechanisms are necessary to prevent DNA damage
from progressing to a mutation that could lead to cancer, but these
same repair mechanisms are used by cancer cells to repair DNA
damaged caused by anti-cancer drugs rendering the drugs less
effective. Left un-repaired, methylation of guanine at the O6 position
would lead to a G-T base pair. MGMT can remove this methylation
allowing for correct base pairing. New cancer therapies are looking at
ways to inactivate MGMT, which would allow the DNA damaging
chemotherapy agents to work better. MDC1 is a potential target for
anti-cancer drugs to inhibit the HR pathway. Inhibition of this protein
leads to a decrease in the signal for repair so the repair machinery to
slow to respond to the damage. Inhibitors of these enzymes along
with traditional therapies would increase the efficacy of the therapies,
but the key is to inhibit the DNA repair mechanisms of the cancer cells
without further damaging the rest of the cells in the body.
REFERENCES:
Esteller M, Herman JG. Generating mutations but providing chemosensitivity: the role
of O6-methylquanine DANA methyltransferase in human cancer. Oncogene 2004;
23:1-8.
Gerson SL. MGMT: Its role in cancer aetiology and cancer therapeutics. Nature Rev.
2004; 4:296-306.
Figure 3. How different methylation backgrounds
of MGMT affect the response to alkylating drugs.
(Esteller et al., 2004)
Iyer, Ravi R., et al. DNA Mismatch Repair: Functions and Mechanisms. Chem. Rev.
2006; 106: 302-323.
Madhusudan, S., and I.D. Hickson. 2005. DNA repair inhibition: a selective tumour
targeting strategy. Trends in Molecular Medicine 2005; 11: 503-511.
Zhang, Junran., et al. MDC1 interacts with Rad51 and facilitates homologous
recombination. Nature: Structural & Molecular Biology 2005; 12: 902-909