DNA Repair Nucleotide Excision Repair XP and CS

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DNA RepairNucleotide Excision Repair XP and CS

• BiS222
• By Jooyoung Chang ???
• Class 01 / Stu. 20091259

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Assembling a Car

• An analogy

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Steps in building a CAR
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Steps in building a PROTEIN
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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

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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!

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Another Example

• RNA polymerase genes
• Copy machine
• DNA to RNA step is JAMMED!
• Cell cannot function
• EX) Cockaynes Syndrome, will be discussed in the
  flash video.

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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

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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!

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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

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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

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Thymine Dimer
Ultraviolet Radiation
Thymine
Thymine
O
O
H
H
H3C
CH3
N
N
Covalent Bonds
H
H
O
O
N
N
DNA Backbone
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Nucleotide Excision Repair
1. Transcription-Coupled Pathway
2. Global Genomic Pathway
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5
3
5
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Nucleotide Excision Repair
TFIIH
XPB
XPD
3
5
3
5
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Nucleotide Excision Repair
XPG
3
5
XPB
XPD
3
5
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Nucleotide Excision Repair
3
5
3
5
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Nucleotide Excision Repair
DNA Polymerase d / e
3
5
3
5
Ligase
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Is NER really important?

• If we want to see whether car tires are
  important,
• Let someone ride a car without it.

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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
• Xeroderma Pigmentosum XP
• Cockaynes Syndrome CS
• (Remember the copy machine?)

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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.

XPC
XPD
XPB
XPG
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Symptoms of XP

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

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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!
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What 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

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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

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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

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REFERENCE

• Karp, Gerald. Cell Biology Pg 291
• Pescarmona, Gianpiero. DNA Breaks and Repair
  lthttp//flipper.diff.org/app/pathways/info/1940gt
• Microsoft Clip Art