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Contents
1- Introduction
2-Repair mechanisms
5- Hereditary DNA repair disorders
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Introduction
DNA repair refers to a collection of processes bywhich a cell identifies and corrects damage to theDNA molecules that encode its genome.
Sources of damage:1-loss of a bases resulting in apurinic/apyrimidinic
(AP) sites (abasic sites).
2-base modifications, such as alkylations or
deamidations(hypozanthin) which convertscytosine, adenine and guanine to uracil.
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3-Replication errors and base conversions can
generate mismatch nucleotide pairs5-Photodamage by uv light can generate
pyrimidine dimers,
6-Chemical agents and reactive oxygen species(ROS) can modify bases .
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Types of DNA Damage Summarised
G A CT
s DNA Break Mismatch
Thymidine dimer
AP site
ss Break
C-U deamination
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DNA Damage & Mutation
DAMAGE
1-Damages are physical
abnormalities in the DNA
2-DNA damages can be
recognized by enzymes,
and, thus, they can be
correctly repaired.
3-If a cell retains DNA damage,
transcription of a gene can
be prevented, and, thus,translation into a protein
will also be blocked
MUTATION
1-A mutation is a change in thebase sequence of the DNA.
2-A mutation cannot berecognized by enzymes
once the base change ispresent in both DNAstrands, and, thus, amutation cannot berepaired.
3-Mutations can causealterations in proteinfunction and regulation.Mutations are replicatedwhen the cell replicates
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REPAIR MECHANISMSIn addition to DNA polymerase 35
exonuclease(the DNA Pol III has proofreadingcapabilities that correct replication mistakes bymeans ofexonuclease activity working 3'->5')..Mammalian cells utilize TWO major DNA repair
pathways:
- single strand damage -db strand breaks
Reverse Excision Non Homo Homo
BER NER MMR
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A-SS damage : 1- reversal ( direct reversal ) :
These mechanisms do not require a template,
since the types of damage they counteract canoccur in only one of the four bases.(this typerepaired without removing abase ornucleotide)
E.X:1-The formation ofpyrimidine dimers upon
irradiation with UV light results in an
abnormal covalent bond between adjacentpyrimidine bases. The photoreactivationprocess directly reverses this damage by theaction of the enzyme photolyase.
http://en.wikipedia.org/wiki/Pyrimidine_dimerhttp://en.wikipedia.org/wiki/Photoreactivationhttp://en.wikipedia.org/wiki/Photolyasehttp://en.wikipedia.org/wiki/Photolyasehttp://en.wikipedia.org/wiki/Photoreactivationhttp://en.wikipedia.org/wiki/Pyrimidine_dimerhttp://en.wikipedia.org/wiki/Pyrimidine_dimerhttp://en.wikipedia.org/wiki/Pyrimidine_dimer7/31/2019 molbio
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Damage Reversal
Photoreactivation (the enzyme DNA potolyase captures energy from light )
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2-Excision : In which the damaged base or bases areremoved and then replaced with the correct ones.
a-Base excision repair :DNA's bases may be modified by deamination or
alkylation. the DNA glycosylase can recognize thedamaged site and remove its base forming AP
site ( Apurinic/ Apyrimidinic). Then, the APendonuclease removes the AP site andneighboring nucleotides. The gap is filled by DNApolymerase I and DNA ligase.
: -Each DNA glycosylase is generally specific for onetype of lesion .
_ Humans have at least four types glycosylase with
different specifictices .
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B- Nucleotide excision repair :
NER differs from BER in several ways:
-It uses different enzymes.-Even though there may be only a single "bad" base
to correct, its nucleotide is removed along withmany other adjacent nucleotides; that is, NER
removes a large "patch" around the damage .- In NER a multisubunit enzyme hydrolyzes two
phosphodiester bonds one on either side of thedistorsion caused by lesion ( in human it
hydrolyzes the 6th bond on 3\ side & the 22 bondon the 5\ end producing a fragment of 27-29nucleotides ) resulting in gap filled by DNApolymerase1 & finally DNA ligase seals the nick .
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5
3
3
5
5
3
3
5
OR
5
3
3
5
UvrABC
5
3
3
5
Pol1
5
3
3
5
5
3
3
5
5
3
3
5
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C- Mismatch repair :
To repair mismatched bases, the system has to
know which base is the correct one. In E. coli,this is achieved by a special methylase calledthe "Dam methylase", which can methylate alladenines that occur within (5')GATC
sequences. Immediately after DNAreplication, the template strand has beenmethylated, but the newly synthesized strand
is not methylated yet. Thus, the templatestrand and the new strand can bedistinguished.
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B- Db strand damage : There are two mechanismsby which the cell attempts to repair a completebreak in a DNA molecule:
1-Direct joining: of the broken ends. This requiresproteins that recognize and bind to the exposedends and bring them together for ligating. Theywould prefer to see some complementary
nucleotides but can proceed without them so thistype of joining is also called NonhomologousEnd-Joining (NHEJ).
Errors in direct joining may be a cause of thevarious translocations that are associated withcancers.
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Defects in the NER mechanism are responsible for
several genetic disorders, including:Xeroderma pigmentosum: hypersensitivity to
sunlight/UV, resulting in increased skin cancerincidence and premature aging
Cockayne syndrome: hypersensitivity to UV andchemical agents
Trichothiodystrophy: sensitive skin, brittle hair andnails
Mental retardation often accompanies the lattertwo disorders, suggesting increased vulnerabilityof developmental neurons.
http://en.wikipedia.org/wiki/Xeroderma_pigmentosumhttp://en.wikipedia.org/wiki/Cockayne_syndromehttp://en.wikipedia.org/wiki/Trichothiodystrophyhttp://en.wikipedia.org/wiki/Trichothiodystrophyhttp://en.wikipedia.org/wiki/Cockayne_syndromehttp://en.wikipedia.org/wiki/Cockayne_syndromehttp://en.wikipedia.org/wiki/Cockayne_syndromehttp://en.wikipedia.org/wiki/Xeroderma_pigmentosumhttp://en.wikipedia.org/wiki/Xeroderma_pigmentosumhttp://en.wikipedia.org/wiki/Xeroderma_pigmentosum7/31/2019 molbio
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Other DNA repair disorders include:
Werner's syndrome: premature aging and
retarded growthBloom's syndrome: sunlight hypersensitivity,
Ataxia telangiectasia: sensitivity to ionizingradiation and some chemical agents .
Huntington disease:Neurologicaldisorder(increased number of glutamin array)
http://en.wikipedia.org/wiki/Werner's_syndromehttp://en.wikipedia.org/wiki/Bloom_syndromehttp://en.wikipedia.org/wiki/Ataxia_telangiectasiahttp://en.wikipedia.org/wiki/Ataxia_telangiectasiahttp://en.wikipedia.org/wiki/Bloom_syndromehttp://en.wikipedia.org/wiki/Werner's_syndrome7/31/2019 molbio
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