DNA REPAIR SYSTEM B10_revisi dr.doc

7/26/2019 DNA REPAIR SYSTEM B10_revisi dr.doc

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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, !!"#.

DNA, li$e any other molecules, can undergo a variety of chemical reactions. %ecause

DNA uni&uely serves as a permanent copy of the cell genome, however, changes in its

structure are of much greater conse&uence than are alterations in other cell components, such

as 'NAs orproteinscalled mutation (eoffrey M. !!!#.

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

fre&uency of about one in every )!* cell divisions (Murray, !!"#. +n addition, various

chemical changes occur in DNA either spontaneously or as a result of exposure to chemicals

or radiation (eoffrey M. !!!#. A number of factors, including viruses, chemicals,

ultraviolet light, and ioniing 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, horiontally#. +t is becoming apparent that a number of diseases-and perhaps

most cancers-are due to the combined effects of vertical transmission of mutations as well

as horiontal transmission of induced mutations (Murray, !!"#. uch damage to DNA can

bloc$ replication or transcription, and can result in a high fre&uency of mutations-

conse&uences that are unacceptable from the standpoint of cell reproduction (eoffrey M.

!!!#. 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

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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, !!"#. +n addition, although genetic variation is important for evolution, the

survival of the individual demands genetic stability. Maintaining genetic stability

re&uires 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 %. !!#.

DNA repair system is the process by which a cell uses a series of special enymesto 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 cascadeof unrepaired mutations in the genome. %ecause DNA damage occurs

spontaneously and as a result to ubi&uitous 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/dna-

repair).

The importance of effective DNA repair systems is highlighted by the severe

diseases affecting people with deficient repair systems (trachan. )"""# and it becomes

evident from the large investment that cells ma$e in DNA repair enymes. /or example,

analysis of the genomes of bacteria and yeasts has revealed that several percent of thecoding 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 them-which we now $now operate in a wide variety of organisms,

including humans-were originally identified in bacteria by the isolation and

characteriation of mutants that displayed an increased mutation rate or an increased

sensitivity to DNA0damaging agents (Alberts %. !!#.

B. Mechanism of DNA Repair System

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http://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5084/http://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5094/http://www.medicinenet.com/script/main/art.asp?articlekey=32065http://increasedlifespan.com/dna-repairhttp://increasedlifespan.com/dna-repairhttp://increasedlifespan.com/dna-repairhttp://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5502/http://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5215/http://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5501/http://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5084/http://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5094/http://www.medicinenet.com/script/main/art.asp?articlekey=32065http://increasedlifespan.com/dna-repairhttp://increasedlifespan.com/dna-repairhttp://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5502/http://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5215/http://www.ncbi.nlm.nih.gov/books/n/mboc4/A4754/def-item/A5501/


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1) Direct Reersa! Repair

Most damage toDNA is repaired by removal of the damaged bases followed by

resynthesis of the excised region. ome 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 fre&uently. 1nly a few types of DNA

damage are repaired in this way, particularly pyrimidine dimers resulting from

exposure to ultraviolet (23# light and al$ylated guanine residues that have been

modified by the addition of methyl or ethyl groups at the 1 *position of the purine

ring.

23 light is one of the ma4or sources of damage to DNAand is also the most

thoroughly studied form of DNA damage in terms of repair mechanisms. +tsimportance is illustrated by the fact that exposure to solar 23 irradiation is the cause

of almost all s$in cancerin humans. The ma4or type of damage induced by 23 light is

the formation ofpyrimidine dimers, in which ad4acent pyrimidines on the same strand

of DNA are 4oined 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 bloc$s transcriptionor replication past the site of damage, so

their repair is closely correlated with the ability of cells to survive 23 irradiation.

1ne mechanism of repairing 230induced pyrimidine dimers is direct reversal of the

dimeriation reaction. The process is calledphotoreactivationbecause energy derived

from visible light is utilied to brea$ 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 23 irradiation is a ma4or source of DNA damage for

diverse cell types, the repair of pyrimidine dimers byphotoreactivationis common to

a variety of pro$aryotic and eu$aryotic cells, includingE. coli,yeasts, and some

species of plants and animals. 5uriously, however, photoreactivation is not universal6

many species (including humans# lac$ this mechanism of DNA repair (eoffrey M.

!!!#.

") Sin#!e$stran% %ama#e

7hen 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. +n order to repair

damage to one of the two paired molecules of DNA, there exist a number of excision

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http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3010/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3010/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3105/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3010/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A2944/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3304/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3304/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3391/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3252/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3252/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3051/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3425/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3425/http://en.wikipedia.org/wiki/Excision_repairhttp://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3010/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3105/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3010/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A2944/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3304/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3391/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3252/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3252/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3051/http://www.ncbi.nlm.nih.gov/books/n/cooper/A2886/def-item/A3425/http://en.wikipedia.org/wiki/Excision_repair


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repairmechanisms that remove the damaged nucleotide and replace it with an

undamaged nucleotide complementary to that found in the undamaged DNA strand

1. Base e&cision repair'BER)

The depurination of DNA, which happens spontaneously owing to the thermal

lability of the purine N0glycosidic bond, occurs at a rate of 8,!!!9

)!,!!!:cell:d at ; Murray, !!"
http://en.wikipedia.org/wiki/Excision_repairhttp://en.wikipedia.org/wiki/Base_excision_repairhttp://en.wikipedia.org/wiki/Excision_repairhttp://en.wikipedia.org/wiki/Base_excision_repair


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which induces the formation of cyclobutane pyrimidinepyrimidine dimers,

and smo$ing, which causes formation of beno?a@pyrene0guanine adducts.

+oniing radiation, cancer chemotherapeutic agents, and a variety of

chemicals found in the environment cause base modification, strand brea$s,

cross0lin$age between bases on opposite strands or between DNA and protein,

and numerous other defects. These are repaired by a process called nucleotide

excision0repair. 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 )*

polypeptides in humans, accomplishes this tas$. +n eu$aryotic cells the

enymes cut between the third to fifth phosphodiester bond ; from the lesion,

and on the 8 side the cut is Thus, a fragment of DNA Murray, !!"


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. Mismatch repair'MMR)

Mismatch repair corrects errors made when DNA is copied. /or example, a 5

could be inserted opposite an A, or the polymerase could slip or stutter and

insert two or more extra unpaired bases. pecific proteins scan the newly

synthesied DNA, using adenine methylation within a AT5 se&uence as the

point of reference. The template strand is methylated, and the newly

synthesied strand is not. This difference allows the repair enymes to identify

the strand that contains the errant nucleotide which re&uires replacement.

+f a mismatch or small loop is found, a AT5 endonuclease cuts the

strand bearing the mutation at a site corresponding to the AT5. An

exonuclease then digests this strand from the AT5 through the mutation,

thus removing the faulty DNA. This can occur from either end if the defect is

brac$eted by two AT5 sites. This defect is then filled in by normal cellular

enymes according to base pairing rules. +nE coli, three proteins (Mut , Mut

5, and Mut # are re&uired for recognition of the mutation and nic$ing of the

strand. 1ther cellular enymes, including ligase, polymerase, and %s,

remove and replace the strand. The process is somewhat more complicated in

mammalian cells, as about six proteins are involved in the first steps.

/aulty mismatch repair has been lin$ed to hereditary nonpolyposis

colon cancer (NC55#, one of the most common inherited cancers. enetic

studies lin$ed NC55 in some families to a region of chromosome . The

gene located, designated hM!", was subse&uently shown to encode the

human analog of theE coli Mut protein that is involved in mismatch repair.

Mutations of hM!" account for 8!9*!F of NC55 cases. Another gene,

hM#!$, is associated with most of the other cases. hM#!$ is the human

analog of the bacterial mismatch repair gene Mut#. The human genes were

localied 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. +t appears that the affected cells, which harbor a

mutated hM!" or hM#!$ mismatch repair enyme, are unable to remove

small loops of unpaired DNA, and the microsatellite thus increases in sie.

2ltimately, 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, !!"#.

) Do(*!e$stran% *rea+s

The repair of double0strand (ds# brea$s is part of the physiologic process of

immunoglobulin gene rearrangement. +t is also an important mechanism for

repairing damaged DNA, such as occurs as a result of ioniing radiation or

oxidative free radical generation. ome chemotherapeutic agents destroy cells

by causing ds brea$s or preventing their repair.

Two proteins are initially involved in the nonhomologous re4oining of

a ds brea$.%u, a heterodimer of

DNA ends and has latent ATCdependent helicase activity. The DNA0bound Hu

heterodimer recruits a uni&ue protein $inase, &'-dependent protein inase

(&'-P%). DNA0CH has a binding site for DNA free ends and another for

dsDNA 4ust inside these ends. +t therefore allows for the approximation of the

two separated ends.

The free end DNA0Hu0DNA0CH complex activates the $inase activityin the latter. DNA0CH reciprocally phosphorylates Hu and the other DNA0CH

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Nucleotide excision0repair. Thismechanism is employed to correctlarger defects in DNA and generallyinvolves more proteins than eithermismatch or base excision0repair. After

defect recognition (indicated byBBBB# and unwinding of the DNAencompassing the defect, an excisionnuclease (exinuclease# cuts the DNAupstream and downstream of thedefective region. This gap is then filled

in by a polymerase (E: in humans# andreligated.

c> Murray, !!"


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molecule, on the opposing strand, in trans. DNA0CH then dissociates from the

DNA and Hu, resulting in activation of the Hu helicase. This results in

unwinding of the two ends. The unwound, approximated DNA forms base

pairs6 the extra nucleotide tails are removed by an exonuclease6 and the gaps

are filled and closed by DNA ligase (Murray, !!"#.

C. M(tation of DNA Repair System an% Its Corre!ation to Cancer

There are two aspects that possibly happen, causes by DNA repair system related to the

cancer disease.

). DNA repair system cannot be used at the time of the system itself undergoes

damage. +n the process of wor$ing DNA repair systems, if the enymes that have

roles in the system are coded by a gene that underwent a mutation and an enyme

that is coded by those genes accumulate in large amount, then can cause cancer.

%ecause during the enyme will serve as DNA repair systems, beside it is

coded by a gene that underwent a mutation, the enyme cannot wor$ properly. +f

an enyme that does not wor$ in a normal way that will cause of cancer disease

upon the human body.

enes are encoded withinDNA,so anything that damages DNAcan increase

the ris$ of cancer. %ut 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 personIs

lifetime. 5ancers that are directly caused by specific genetic faults inherited from

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Double0strand brea$ repair ofDNA. The proteins Hu andDNA0dependent protein $inasecombine to approximate the two

strands and unwind them. Thealigned fragments form basepairs6 the extra ends areremoved, probably by a DNA0CH0associated endo0 or exonuclease, and the gaps are

filled in6 and continuity isrestored by ligation.

c> Murray, !!"
http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/what-causes-cancer/ssNODELINK/DNAdamagerepairhttp://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/what-causes-cancer/ssNODELINK/DNAdamagerepair


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a parent are rare. %ut we all have subtle variations in our genes that may increase

or decrease our ris$ of cancer by a small amount (http://www.cancerresearchu.org).

. There is a therapy for cancer with Al$ylating Agents. Al$ylating agents are a

large class of chemotherapeutic drugs and play an important role in the treatment

of several types of cancer. %ecause of the Al$ylating Agents function for cancer

treatment, in this case, DNA repair system is not expected to wor$. o the

Al$ylating Agents can wor$ properly and ma$es the cancer cell experience

apoptosis. Apoptosisis a form of cell death in which a programmed se&uence of

events leads to the elimination of cells without releasing harmful substances into

the surrounding area .

CONC,USION

DNA repair system is the process by which a cell uses a series of special enymes 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 DNArepair 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 ma$e in DNA repair enymes.

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(%J'#, nucleotide excision repair (NJ'#, and mismatch repair(MM'#

and the last is double0strand brea$s.

ome lesions in DNA, however, can be repaired by direct reversal of the damage

through the process calledphotoreactivation. The Mismatch repair occurs if there is the event

of copying errors (single base or two0 to five0base unpaired loops# and repaired by methyl0

directed strand cutting, exonuclease digestion, and replacement. %ase excision repair is

caused by spontaneous, chemical, or radiation damage to a single base. +t can be cured

through base removal by '-glycosylase, abasic sugar removal, then could be replaced.

Nucleotide excision9repair is caused by pontaneous, chemical, or radiation damage to a DNA

segment then be able to prevent by removing of an approximately ;!0nucleotide oligomer

and replacement. Double0strand brea$ repair occurs because of ioniing 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, al$ylating

agents are a large class of chemotherapeutic drugs and play an important role in the treatment

of several types of cancer. %ecause of the Al$ylating Agents function for cancer treatment, in

this case, DNA repair system is not expected to wor$.

RE-ERENCES

Alberts %, etc. !!.Molecular *iolog+ of the ,ell. Kthed.New Lor$> arland cience.

5ooper, eoffrey M. !!!. he ,ell: Molecular pproach. nded. underland>inauer

Associates.+%N0)!> !0G


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Murray, 'obert H, etc. !!".!arpers llustrated *iochemistr+. Gthed. New Lor$> Mcraw0

ill. +%N "

arland cience.

INTERNET SITES

http://www.cancerresearchu.org/cancer-info/cancerandresearch/all-a1out-cancer/what-is-

cancer/what-causes-cancer/

http://www.cancerresearchu.org/cancer-info/cancerandresearch/all-a1out-cancer/what-is-

cancer/treating-cancer/

http://www.medicinenet.com/script/main/art.asp2articlee+34567

http://increasedlifespan.com/dna-repair

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http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/what-causes-cancer/http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/what-causes-cancer/http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/treating-cancer/http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/treating-cancer/http://www.medicinenet.com/script/main/art.asp?articlekey=3095http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/what-causes-cancer/http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/what-causes-cancer/http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/treating-cancer/http://www.cancerresearchuk.org/cancer-info/cancerandresearch/all-about-cancer/what-is-cancer/treating-cancer/http://www.medicinenet.com/script/main/art.asp?articlekey=3095

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