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DNA Repair Farina PDF
DNA Repair Farina PDF
The End!
DNA REPAIR
DNA is the only biological molecule that
is repaired
DNA damage
Alteration to the chemical structure of
DNA
Mutation
Change in the sequence of DNA
NATURE OF DNA DAMAGE
Loss of bases
Modification of bases
Inter/intra-strand crosslinks
DNA strand breakage (single and
double strand)
CAUSES OF DNA DAMAGE
Endogenous factors
Spontaneous
- Errors in proofreading
- Deamination of bases
- Depurination/Depyrimidination
Induced
- Byproducts of normal cellular processes
(reactive oxygen species etc )
Exogenous factors
- UV irradiation (sunlight)
- High energy irradiation (x-rays)
- Mutagenic chemicals (Mustard gas, cigarette
smoke, food additives)
ERRORS IN PROOFREADING
1000 bases/second =
lots of typos!
Replication = 10-3
Proofreading= 10-6
3’-5’ exonuclease activity
C T U T C
Deamination Mutation
GA A AG
New strand
C T U
C T C DNA
Replication
GAGAG
New strand
C T C T C
Unchanged
GAGAG
Parental strand
DEPURINATION/
DEPYRIMIDINATION
• Cleavage of the glycosidic bond removes
bases
C T C T C
GAG G
C T C C
AP site Mutation
GAG G
Parental strand
REACTIVE OXYGEN SPECIES
Generated during normal aerobic respiration
– Superoxides, O2-,
.
– Hydroxyl ions (OH )
– H2O2
Guanine 8-oxodG
Exogenous – UV IRRADIATION
Dimerizes adjacent
thymine residues.
The dimer creates a
kink in the DNA that
blocks the
progression DNA
polymerase
HIGH-ENERGY RADIATION
X-rays and gamma rays may directly
break DNA strands
Recognition of damage
Removal of damage
Resynthesis of gap
Ligation
EXCISION REPAIR
Two types of excision repairs
• Base Excision Repair
Repair of methylated, deaminated, oxidized
bases and AP sites.
Glycosylase
AP Lyase
endonuclease
DNA polymerase
DNA ligase
NUCLEOTIDE EXCISION REPAIR
Thymine dimer
UvrAB excinuclease
A A
B
UvrC excinuclease
A A
B HvrD Helicase
DNA polymerase
DNA ligase
No thymine dimer
NER ASSOCIATED DISEASES
• Xeroderma pigmentosum
• Cockayne Syndrome
• PIBIDS (photosensitivity, ichthyosis, brittle
hair, impaired intelligence, decreased
fertility, short stature)
MutS/MutL
DNA Polymerase
CH3 CH3
DNA Ligase
CH3 CH3
HEREDITARY NONPOLYPOSIS
COLORECTAL CANCER (HNPCC)
• Lynch syndrome
• Accounts for 2 -10% of all colon
cancers
• Caused by defects in mismatch repair
genes.
☺ Direct repair
DNA STRAND BREAKS
DNA STRAND BREAKS
• 10 -100 naturally occurring double-strand
breaks per cell per day