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DNA Repair Nucleotide Excision Repair XP and CS

DNA Repair Nucleotide Excision Repair XP and CS. BiS222 By Jooyoung Chang 장주영 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)

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DNA Repair Nucleotide Excision Repair XP and CS

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  1. DNA RepairNucleotide Excision Repair XP and CS BiS222 By Jooyoung Chang 장주영 Class #01 / Stu. #20091259

  2. Assembling a Car An analogy

  3. Steps in building a CAR

  4. Steps in building a PROTEIN

  5. Q: Most devastating effect? • Mistake in the Blueprint! • Toyota (Jan. 2010) • Massive recall foot pedal • Mistake in blueprint-level • DNA Damage • Has devastating effects • DNA is the starting point of protein production, thus cell function

  6. DNA Damage Example • Tumor suppressor genes • Gene that encodes protein: p53 • Recognizes damaged DNA • And prevents mutant cell from replicating • If p53 is damaged • Mutated cells grow uncontrollably • And become tumorous!

  7. Another Example • RNA polymerase genes • Copy machine • DNA to RNA step is JAMMED! • Cell cannot function • EX) Cockayne’s Syndrome, will be discussed in the flash video. JAMMED!

  8. DNA is Fragile • Ionizing radiation often breaks DNA strands • Reactive chemicals, many of which are from the cell itself, cause structural alteration • UV radiation causes chemical alterations • Even thermal energy from the cell can cause spontaneous alterations, or lesions

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

  10. Repair Mechanisms • Base Excision Repair • Multi-step process that corrects non-bulky damage • Mismatch Repair • Corrects DNA replication errors • Double stranded breakage repair • Repairs complete cuts in the DNA strand • Nucleotide excision repair (NER) • Removes bulky lesions in the cell

  11. Nucleotide Excision Repair • NER is perhaps the most flexible of the DNA repair pathways considering the diversity of DNA lesions it acts upon. • Pyrimidine dimers • Nucleotides with altered chemistry • Thymine dimers

  12. Thymine Dimer Ultraviolet Radiation Thymine Thymine O O H H CH3 H3C N N Covalent Bonds H H O O N N DNA Backbone

  13. Nucleotide Excision Repair 1. Transcription-Coupled Pathway 2. Global Genomic Pathway CSA CSB XPC RNA Polymerase 3’ 5’ T = T 3’ 5’ RNA

  14. Nucleotide Excision Repair TFIIH XPB XPD 3’ 5’ T = T 3’ 5’ Hydrogen bonds

  15. Nucleotide Excision Repair XPF XPG ERCC1 3’ 5’ T = T XPB XPD 3’ 5’

  16. Nucleotide Excision Repair XPF ERCC1 3’ 5’ XPG T = T XPB XPD 3’ 5’

  17. Nucleotide Excision Repair DNA Polymerase δ / ε 3’ 5’ 3’ 5’ Ligase

  18. Is NER really important? • If we want to see whether car tires are important, • Let someone ride a car without it.

  19. 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 diseases • XerodermaPigmentosum [XP] • Cockayne’s Syndrome [CS] (Remember the copy machine?)

  20. What goes wrong in XP? • Patients with XerodermaPigmentosum have mutated XP genes and cannot make proper XP enzymes. • NER doesn’t function at normal levels, DNA damage is not repaired well, many genes cannot be used. XPC XPF XPD ERCC1 XPB XPG

  21. Symptoms of XP • Skin- sunburns and freckles • Cancer/Carcinoma- damaged tumor suppressor genes (1000 fold risk) • Eye abnormalities • Neurological Disorders in severe cases

  22. Treatments? • Avoid sunlight and wear protective coverings • Dimericine® -T4N5 Liposome Lotion (FDA Fast Track Designation) • Gene therapy using recombinant retroviruses – still under development Proper XP genes T4N5 VIRUS XP affected Cell NER restored!

  23. What goes wrong in CS? • Cockayne’s 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

  24. Symptoms of CS • Mutated CSA and CSB likely hinder transcription mechanisms affecting damaged and undamaged DNA alike • Dwarfism, photosensitivity disorders, premature aging, and hearing loss • No cure, treatment focuses on relief

  25. Key points to take away • DNA 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

  26. REFERENCE Karp, Gerald. “Cell Biology” Pg 291 Pescarmona, Gianpiero. “DNA Breaks and Repair” <http://flipper.diff.org/app/pathways/info/1940> Microsoft Clip Art

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