DNA Repair Nucleotide Excision Repair XP and CS

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DNA Repair Nucleotide Excision Repair XP and CS. BiS222 By Jooyoung Chang Class #01 / Stu. #20091259. Assembling a Car. An analogy. Steps in building a CAR. Steps in building a PROTEIN. Q: Most devastating effect?. Mistake in the Blueprint! Toyota (Jan. 2010) - PowerPoint PPT Presentation

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DNA Repair Nucleotide Excision Repair XP and CS

DNA RepairNucleotide Excision Repair XP and CSBiS222By Jooyoung Chang Class #01 / Stu. #20091259Assembling a CarAn analogySteps in building a CAR

Steps in building a PROTEIN

Q: Most devastating effect?Mistake in the Blueprint!Toyota (Jan. 2010)Massive recall foot pedalMistake in blueprint-levelDNA DamageHas devastating effectsDNA is the starting point of protein production, thus cell function

DNA Damage ExampleTumor suppressor genesGene that encodes protein: p53Recognizes damaged DNAAnd prevents mutant cell from replicating

If p53 is damagedMutated cells grow uncontrollablyAnd become tumorous!

To make matters worse,6Another ExampleRNA polymerase genesCopy machineDNA to RNA step is JAMMED!Cell cannot functionEX) Cockaynes Syndrome, will be discussed in the flash video.

JAMMED!

To make matters worse,7DNA is Fragile Ionizing radiation often breaks DNA strandsReactive chemicals, many of which are from the cell itself, cause structural alterationUV radiation causes chemical alterationsEven thermal energy from the cell can cause spontaneous alterations, or lesions

DNA Repair to the Rescue!The cell has a remarkable ability to repair DNAThese DNA repair mechanisms are responsible for repairing thousands of DNA alterations per day!

Repair MechanismsBase Excision RepairMulti-step process that corrects non-bulky damageMismatch RepairCorrects DNA replication errorsDouble stranded breakage repairRepairs complete cuts in the DNA strandNucleotide excision repair (NER)Removes bulky lesions in the cellNucleotide Excision RepairNER is perhaps the most flexible of the DNA repair pathways considering the diversity ofDNAlesions it acts upon.Pyrimidine dimersNucleotides with altered chemistryThymine dimers

Thymine DimerHHH3COONNNHHCH3OONUltraviolet RadiationCovalent BondsDNA Backbone

ThymineThymine

A thymine dimer is a type of damage caused by UV radiation.Upon exposure to sunlight, two covalent bonds form between two thymine bases in a DNA strand.This dimer causes a protrusion in the DNA backbone which stops the cell from using it.12RNARNA PolymeraseCSA CSBXPCNucleotide Excision RepairTT=55331. Transcription-Coupled Pathway2. Global Genomic Pathway

Nucleotide Excision Repair or NER is a mechanism that can repair this damage.It separates into two pathways. One is a transcription-couple pathway in which active DNA strands are repaired as they are being used by RNA polymerase. The polymerase is halted by the protrusion caused by the thymine dimer. This pathway gives repair precedence to genes with highest priority.The other global genomic path repairs all other strands.13XPBXPDNucleotide Excision RepairTT=5533Hydrogen bondsTFIIH

After recognition, the pathways converge. Two enzymes, subunits of a transcription factor complex, cut the hydrogen bonds that hold the double stranded DNA together14XPBXPDXPGERCC1XPFNucleotide Excision RepairTT=5533

Then two endonucleases, or DNA cutters, cut the damaged DNA strand.15XPBXPGERCC1XPFTT=XPDNucleotide Excision Repair5533

Then the whole complex is excised.16DNA Polymerase / Nucleotide Excision Repair5533Ligase

And DNA polymerase, or a DNA maker, makes a new strand of DNA that fills the gap. Ligase finally ligates, or links, the 3 end.17Is NER really important?If we want to see whether car tires are important,Let someone ride a car without it.

Is NER really important?If we want to see whether NER is important,Let see what goes wrong in a cell and the organism when NER is dysfunctional!Two diseasesXeroderma Pigmentosum [XP]Cockaynes Syndrome [CS] (Remember the copy machine?)What goes wrong in XP?Patients with Xeroderma Pigmentosum have mutated XP genes and cannot make proper XP enzymes.NER doesnt function at normal levels, DNA damage is not repaired well, many genes cannot be used.

XPBXPDXPGERCC1XPFXPC

Patient with xeroderma pigmentosum have mutated XP genes and cannot make proper XP enzymes.NER doesnt function, DNA damage remain untouched, and many genes cannot be used.20Symptoms of XPSkin- sunburns and frecklesCancer/Carcinoma- damaged tumor suppressor genes (1000 fold risk)Eye abnormalitiesNeurological Disorders in severe cases

This causes symptoms of severe sunburns and freckling.And when genes that prohibit cancer are damaged, cells can become cancerous. XP patients have almost a 1000-fold risk of developing skin cancer.Others symptoms include eye abnormalities and nero.. Disorders in severe cases21Treatments?Avoid sunlight and wear protective coveringsDimericine -T4N5 Liposome Lotion (FDA Fast Track Designation)Gene therapy using recombinant retroviruses still under development

XP affected CellProper XP genes

VIRUS

NER restored!T4N5

A treatment of XP is to simply avoid sunlight and wear pro. Coverings.Another is Dimericine dissolves T4N5 bacterial DNA repair enzymes into the skin by using bio-capsules called liposomes.Still a developing treatment is to use gene theraphy where proper XP genes are inserted into the cells genome.22What goes wrong in CS?Cockaynes Syndrome is caused by mutation CSA and CSB genes Only the transcription coupled pathway is impaired so active genes cannot be transcribed.Global pathway is unchanged normalrisks of cancer

Cockaynes Syndrome is caused by mutation CSA and CSB genes.Only the transcription coupled pathway is impaired so active genes, ones with highest priority, cannot be transcribed.However, unlike XP, the global pathway is left unchanged, this presumably accounts for normal levels of cancer.23Symptoms of CSMutated CSA and CSB likely hinder transcription mechanisms affecting damaged and undamaged DNA alikeDwarfism, photosensitivity disorders, premature aging, and hearing lossNo cure, treatment focuses on relief

Impairing DNA repair mechanisms, the mutations in CS are likely to also hinder transcription mechanisms whose effect reaches to damaged and undamaged DNA alikeThus, CS patients suffer Dwarfism, photosensitivity disorders, premature aging, and hearing lossThere is no cure for Cockayne syndrome, so treatment focuses on relieving symptoms and improving the patients quality of life.24Key points to take awayDNA is under constant threat of damage

Cells repair DNA as its used (transcribed)

Cells repair DNA in the inactive state

Malfunction in repair mechanisms lead to life-threatening diseases

One point is that DNA is under constant threat of damage.25REFERENCEKarp, Gerald. Cell Biology Pg 291Pescarmona, Gianpiero. DNA Breaks and Repair Microsoft Clip Art

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