INTRODUCTION

The genetic information in the DNA of a chromosome can be transmitted by exact replication
or it can be exchanged by a number of processes, including crossing over, recombination,
transposition, and conversion. These provide a means of ensuring adaptability and diversity
for the organism but, when these processes go awry, can also result in disease (Murray, 2009).
DNA, like any other molecules, can undergo a variety of chemical reactions. Because
DNA uniquely serves as a permanent copy of the cell genome, however, changes in its
structure are of much greater consequence than are alterations in other cell components, such
as RNAs or proteins called mutation (Geoffrey M. 2000).
Mutations can result from the incorporation of incorrect bases during DNA replication
and may result from the faulty replication, movement, or repair of DNA and occur with a
frequency of about one in every 106 cell divisions (Murray, 2009). In addition, various
chemical changes occur in DNA either spontaneously or as a result of exposure to chemicals
or radiation (Geoffrey M. 2000). A number of factors, including viruses, chemicals,
ultraviolet light, and ionizing radiation, increase the rate of mutation. Mutations often affect
somatic cells and so are passed on to successive generations of cells, but only within an
organism (ie, horizontally). It is becoming apparent that a number of diseasesand perhaps
most cancersare due to the combined effects of vertical transmission of mutations as well
as horizontal transmission of induced mutations (Murray, 2009). Such damage to DNA can
block replication or transcription, and can result in a high frequency of mutations
consequences that are unacceptable from the standpoint of cell reproduction (Geoffrey M.
2000). To maintain the integrity of their genomes, cells have therefore had to evolve
mechanisms to repair damaged DNA.
This paper is going to discuss about the definition of DNA repair system, the
mechanism of repairing the mismatch in DNA through DNA repair, and the mutation of DNA
repair system coded by mutant gen that be able to cause cancer as the manifestation of
mutation itself.

CONTENTS

A. Definition of DNA Repair System

The maintenance of the integrity of the information in DNA molecules is of utmost
importance to the survival of a particular organism as well as to survival of the species.
Thus, it can be concluded that surviving species have evolved mechanisms for repairing
DNA damage occurring as a result of either replication errors or environmental insults
(Murray, 2009). In addition, although genetic variation is important for evolution, the
survival of the individual demands genetic stability. Maintaining genetic stability
requires not only an extremely accurate mechanism for replicating DNA, but also
mechanisms for repairing the many accidental lesions that occur continually in DNA.
Most such spontaneous changes in DNA are temporary because they are immediately
corrected by a set of processes that are collectively called DNA repair (Alberts B. 2002).
DNA repair system is the process by which a cell uses a series of special enzymes
to repair mutations (changes) in DNA and restore the DNA to its original state. The DNA
is constantly mutating and being repaired. This repair process is controlled by special
genes. A mutation in a DNA repair gene can cripple the repair process and cause
a cascade of unrepaired mutations in the genome. Because DNA damage occurs
spontaneously and as a result to ubiquitous environmental agents, most organisms
possess some capacity to repair their DNA and DNA is the only macromolecule which is
repaired by cells (http://www.medicinenet.com).
The DNA repair process is constantly active as it responds to damage in the DNA
structure. The rate of DNA repair is dependent on many factors, including the cell type,
the age of the cell, and the extracellular environment (http://increasedlifespan.com/dnarepair).
The importance of effective DNA repair systems is highlighted by the severe
diseases affecting people with deficient repair systems (Strachan. 1999) and it becomes
evident from the large investment that cells make in DNA repair enzymes. For example,
analysis of the genomes of bacteria and yeasts has revealed that several percent of the
coding capacity of these organisms is devoted solely to DNA repair functions. The
importance of DNA repair is also demonstrated by the increased rate of mutation that
follows the inactivation of a DNA repair gene. Many DNA repair pathways and the genes
that encode themwhich we now know operate in a wide variety of organisms,
including humanswere originally identified in bacteria by the isolation and
characterization of mutants that displayed an increased mutation rate or an increased
sensitivity to DNA-damaging agents (Alberts B. 2002).
B. Mechanism of DNA Repair System
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1) Direct Reversal Repair

Most damage to DNA is repaired by removal of the damaged bases followed by
resynthesis of the excised region. Some lesions in DNA, however, can be repaired by
direct reversal of the damage, which may be a more efficient way of dealing with
specific types of DNA damage that occur frequently. Only a few types of DNA
damage are repaired in this way, particularly pyrimidine dimers resulting from
exposure to ultraviolet (UV) light and alkylated guanine residues that have been
modified by the addition of methyl or ethyl groups at the O 6 position of the purine
ring.
UV light is one of the major sources of damage to DNA and is also the most
thoroughly studied form of DNA damage in terms of repair mechanisms. Its
importance is illustrated by the fact that exposure to solar UV irradiation is the cause
of almost all skin cancer in humans. The major type of damage induced by UV light is
the formation of pyrimidine dimers, in which adjacent pyrimidines on the same strand
of DNA are joined by the formation of a cyclobutane ring resulting from saturation of
the double bonds between carbons .The formation of such dimers distorts the structure
of the DNA chain and blocks transcription or replication past the site of damage, so
their repair is closely correlated with the ability of cells to survive UV irradiation.
One mechanism of repairing UV-induced pyrimidine dimers is direct reversal of the
dimerization reaction. The process is called photoreactivation because energy derived
from visible light is utilized to break the cyclobutane ring structure. The original
pyrimidine bases remain in DNA, now restored to their normal state. As might be
expected from the fact that solar UV irradiation is a major source of DNA damage for
diverse cell types, the repair of pyrimidine dimers by photoreactivation is common to
a variety of prokaryotic and eukaryotic cells, including E. coli, yeasts, and some
species of plants and animals. Curiously, however, photoreactivation is not universal;
many species (including humans) lack this mechanism of DNA repair (Geoffrey M.
2000).
2) Single-strand damage
When only one of the two strands of a double helix has a defect, the other strand can
be used as a template to guide the correction of the damaged strand. In order to repair
damage to one of the two paired molecules of DNA, there exist a number of excision

repair mechanisms that remove the damaged nucleotide and replace it with an
undamaged nucleotide complementary to that found in the undamaged DNA strand
1. Base excision repair (BER)
The depurination of DNA, which happens spontaneously owing to the thermal
lability of the purine N-glycosidic bond, occurs at a rate of 5,000
10,000/cell/d at 37C. Specific enzymes recognize a depurinated site and
replace the appropriate purine directly, without interruption of the
phosphodiester backbone.
Cytosine, adenine, and guanine bases in DNA spontaneously form
uracil, hypoxanthine, or xanthine, respectively. Since none of these normally
exist in DNA, it is not surprising that specific N-glycosylases can recognize
these abnormal bases and remove the base itself from the DNA. This removal
marks the site of the defect and allows an apurinic or apyrimidinic
endonuclease to excise the abasic sugar. The proper base is then replaced by a
repair DNA polymerase, and a ligase returns the DNA to its original state).
This series of events is called base excision-repair. By a similar series of steps
involving initially the recognition of the defect, alkylated bases and base
analogs can be removed from DNA and the DNA returned to its original
informational content. This mechanism is suitable for replacement of a single
base but is not effective at replacing regions of damaged DNA (Murray,
2009).
Base excision-repair of DNA. The
enzyme uracil DNA glycosylase
removes the uracil created by
spontaneous deamination of cytosine
in the DNA. An endonuclease cuts the
backbone near the defect; then, after an
endonuclease removes a few bases, the
defect is filled in by the action of a
repair polymerase and the strand is
rejoined by a ligase. (Courtesy of B
Alberts.)
Sc: Murray, 2009

2. Nucleotide-excision repair systems

This mechanism is used to replace regions of damaged DNA up to 30 bases in
length. Common causes of such DNA damage include ultraviolet (UV) light,

which induces the formation of cyclobutane pyrimidinepyrimidine dimers,

and smoking, which causes formation of benzo[a]pyrene-guanine adducts.
Ionizing radiation, cancer chemotherapeutic agents, and a variety of
chemicals found in the environment cause base modification, strand breaks,
cross-linkage between bases on opposite strands or between DNA and protein,
and numerous other defects. These are repaired by a process called nucleotide
excision-repair. This process, which involves more gene products than the two
other types of repair, essentially involves the hydrolysis of two
phosphodiester bonds on the strand containing the defect. A special excision
nuclease (exinuclease), consisting of at least three subunits in E coli and 16
polypeptides in humans, accomplishes this task. In eukaryotic cells the
enzymes cut between the third to fifth phosphodiester bond 3 from the lesion,
and on the 5 side the cut is Thus, a fragment of DNA 2729 nucleotides long
is excised.
After the strand is removed it is replaced, again by exact base pairing,
through the cooperative action of multiple replicative and repair DNA
polymerase, and the ends are joined to the existing strands by DNA ligase.
Xeroderma pigmentosum (XP) is an autosomal recessive genetic disease. The
clinical syndrome includes marked sensitivity to sunlight (ultraviolet) with
subsequent formation of multiple skin cancers and premature death. In
individuals with XP the risk of developing skin cancer is increased 1000- to
2000-fold. The inherited defect seems to involve the repair of damaged DNA,
particularly thymine dimers. Cells cultured from patients with xeroderma
pigmentosum exhibit low activity for the nucleotide excision-repair process.
Seven complementation groups have been identified using hybrid cell
analyses, so at least seven gene products (XPAXPG) are involved. Two of
these (XPA and XPC) are involved in recognition and excision. XPB and
XPD are helicases and, interestingly, are subunits of the transcription factor
TFIIH (Murray, 2009).

Nucleotide
excision-repair.
This
mechanism is employed to correct
larger defects in DNA and generally
involves more proteins than either
mismatch or base excision-repair. After
defect recognition (indicated by
XXXX) and unwinding of the DNA
encompassing the defect, an excision
nuclease (exinuclease) cuts the DNA
upstream and downstream of the
defective region. This gap is then filled
in by a polymerase (/ in humans) and 5
religated.
Sc: Murray, 2009

3. Mismatch repair (MMR)

Mismatch repair corrects errors made when DNA is copied. For example, a C
could be inserted opposite an A, or the polymerase could slip or stutter and
insert two or more extra unpaired bases. Specific proteins scan the newly
synthesized DNA, using adenine methylation within a GATC sequence as the
point of reference. The template strand is methylated, and the newly
synthesized strand is not. This difference allows the repair enzymes to identify
the strand that contains the errant nucleotide which requires replacement.
If a mismatch or small loop is found, a GATC endonuclease cuts the
strand bearing the mutation at a site corresponding to the GATC. An
exonuclease then digests this strand from the GATC through the mutation,
thus removing the faulty DNA. This can occur from either end if the defect is
bracketed by two GATC sites. This defect is then filled in by normal cellular
enzymes according to base pairing rules. In E coli, three proteins (Mut S, Mut
C, and Mut H) are required for recognition of the mutation and nicking of the
strand. Other cellular enzymes, including ligase, polymerase, and SSBs,
remove and replace the strand. The process is somewhat more complicated in
mammalian cells, as about six proteins are involved in the first steps.
Faulty mismatch repair has been linked to hereditary nonpolyposis
colon cancer (HNPCC), one of the most common inherited cancers. Genetic
studies linked HNPCC in some families to a region of chromosome 2. The
gene located, designated hMSH2, was subsequently shown to encode the
human analog of the E coli MutS protein that is involved in mismatch repair.
Mutations of hMSH2 account for 5060% of HNPCC cases. Another gene,
hMLH1, is associated with most of the other cases. hMLH1 is the human
analog of the bacterial mismatch repair gene MutL. The human genes were
localized because microsatellite instability was detected. That is, the cancer
cells had a microsatellite of a length different from that found in the normal
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cells of the individual. It appears that the affected cells, which harbor a
mutated hMSH2 or hMLH1 mismatch repair enzyme, are unable to remove
small loops of unpaired DNA, and the microsatellite thus increases in size.
Ultimately, microsatellite DNA expansion mustaffect either the expression or
the function of a protein critical in surveillance of the cell cycle in these colon
cells (Murray, 2009).

Nucleotide
excision-repair.
This
mechanism is employed to correct
larger defects in DNA and generally
involves more proteins than either
mismatch or base excision-repair. After
defect recognition (indicated by
XXXX) and unwinding of the DNA
encompassing the defect, an excision
nuclease (exinuclease) cuts the DNA
upstream and downstream of the
defective region. This gap is then filled
in by a polymerase (/ in humans) and
religated.
Sc: Murray, 2009

3) Double-strand breaks
The repair of double-strand (ds) breaks is part of the physiologic process of
immunoglobulin gene rearrangement. It is also an important mechanism for
repairing damaged DNA, such as occurs as a result of ionizing radiation or
oxidative free radical generation. Some chemotherapeutic agents destroy cells
by causing ds breaks or preventing their repair.
Two proteins are initially involved in the nonhomologous rejoining of
a ds break. Ku, a heterodimer of 70-kDa and 86-kDa subunits, binds to free
DNA ends and has latent ATPdependent helicase activity. The DNA-bound Ku
heterodimer recruits a unique protein kinase, DNA-dependent protein kinase
(DNA-PK). DNA-PK has a binding site for DNA free ends and another for
dsDNA just inside these ends. It therefore allows for the approximation of the
two separated ends.
The free end DNA-Ku-DNA-PK complex activates the kinase activity
in the latter. DNA-PK reciprocally phosphorylates Ku and the other DNA-PK
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molecule, on the opposing strand, in trans. DNA-PK then dissociates from the
DNA and Ku, resulting in activation of the Ku helicase. This results in
unwinding of the two ends. The unwound, approximated DNA forms base
pairs; the extra nucleotide tails are removed by an exonuclease; and the gaps
are filled and closed by DNA ligase (Murray, 2009).
Double-strand break repair of
DNA. The proteins Ku and
DNA-dependent protein kinase
combine to approximate the two
strands and unwind them. The
aligned fragments form base
pairs; the extra ends are
removed, probably by a DNAPK-associated
endoor
exonuclease, and the gaps are
filled in; and continuity is
restored by ligation.
Sc: Murray, 2009

C. Mutation of DNA Repair System and Its Correlation to Cancer

There are two aspects that possibly happen, causes by DNA repair system related to the
cancer disease.
1. DNA repair system cannot be used at the time of the system itself undergoes
damage. In the process of working DNA repair systems, if the enzymes that have
roles in the system are coded by a gene that underwent a mutation and an enzyme
that is coded by those genes accumulate in large amount, then can cause cancer.
Because during the enzyme will serve as DNA repair systems, beside it is
coded by a gene that underwent a mutation, the enzyme cannot work properly. If
an enzyme that does not work in a normal way that will cause of cancer disease
upon the human body.
Genes are encoded withinDNA, so anything that damages DNA can increase
the risk of cancer. But a number of genes in the same cell need to be damaged
before it becomes cancerous.
Most cancers are caused by DNA damage that accumulates over a person's
lifetime. Cancers that are directly caused by specific genetic faults inherited from

a parent are rare. But we all have subtle variations in our genes that may increase
or decrease our risk of cancer by a small amount (http://www.cancerresearchuk.org).

2. There is a therapy for cancer with Alkylating Agents. Alkylating agents are a
large class of chemotherapeutic drugs and play an important role in the treatment
of several types of cancer. Because of the Alkylating Agents function for cancer
treatment, in this case, DNA repair system is not expected to work. So the
Alkylating Agents can work properly and makes the cancer cell experience
apoptosis. Apoptosis is a form of cell death in which a programmed sequence of
events leads to the elimination of cells without releasing harmful substances into
the surrounding area .

CONCLUSION
DNA repair system is the process by which a cell uses a series of special enzymes to repair
mutations (changes) in DNA and restore the DNA to its original state. The DNA repair
process is constantly active as it responds to damage in the DNA structure. The rate of DNA
repair is dependent on many factors, including the cell type, the age of the cell, and the
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extracellular environment and the importance of DNA repair is evident from the large
investment that cells make in DNA repair enzymes.
The mechanism of DNA repair system is devided into two type, the first is direct
repair system, then followed by single strand damage included three mechanisms, those are
base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR)
and the last is double-strand breaks.
Some lesions in DNA, however, can be repaired by direct reversal of the damage
through the process called photoreactivation. The Mismatch repair occurs if there is the event
of copying errors (single base or two- to five-base unpaired loops) and repaired by methyldirected strand cutting, exonuclease digestion, and replacement. Base excision repair is
caused by spontaneous, chemical, or radiation damage to a single base. It can be cured
through base removal by N-glycosylase, abasic sugar removal, then could be replaced.
Nucleotide excisionrepair is caused by pontaneous, chemical, or radiation damage to a DNA
segment then be able to prevent by removing of an approximately 30-nucleotide oligomer
and replacement. Double-strand break repair occurs because of ionizing radiation,
chemotherapy, oxidative free radicals and treated by synapsis, unwinding, alignment,
ligation.
DNA repair system cannot be used at the time of the system itself undergoes damage
and if it is encoded by mutant gen, it will activate the cancer. The other case, alkylating
agents are a large class of chemotherapeutic drugs and play an important role in the treatment
of several types of cancer. Because of the Alkylating Agents function for cancer treatment, in
this case, DNA repair system is not expected to work.

REFERENCES
Alberts B, etc. 2002. Molecular Biology of the Cell. 4th ed. New York: Garland Science.
Cooper, Geoffrey M. 2000. The Cell: A Molecular Approach. 2nd ed. Sunderland: Sinauer
Associates. ISBN-10: 0-87893-106-6
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Murray, Robert K, etc. 2009. Harpers Illustrated Biochemistry. 28th ed. New York: McGrawHill. ISBN 978-0-07-170197-6
Strachan, Tom, Andrew P Read. 1999. Human Molecular Genetics. 2nd ed. New York:
Garland Science.

INTERNET SITES
http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-iscancer/what-causes-cancer/
http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-iscancer/treating-cancer/
http://www.medicinenet.com/script/main/art.asp?articlekey=3095
http://increasedlifespan.com/dna-repair

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