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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.

http://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/Cell_(biology)

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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

http://en.wikipedia.org/wiki/Exonucleasehttp://en.wikipedia.org/wiki/Exonuclease

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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_dimer

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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 .

http://www.web-books.com/MoBio/Free/Ch7F6.htmhttp://www.web-books.com/MoBio/Free/Ch7F.htmhttp://www.web-books.com/MoBio/Free/Ch7F6.htmhttp://www.web-books.com/MoBio/Free/Ch7F6.htmhttp://www.web-books.com/MoBio/Free/Ch7F.htm

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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_pigmentosum

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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_syndrome

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