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DNA mutation and repair

Books
• Genes VII by B
...

• Molecular biology of the gene, J
...

• General biochemistry books

What is a mutation?
• A mutation is a change in base sequence in genetic
material
• May be silent
– No phenotypic change
• Phenotype is the visible manifestation of a trait

• May be beneficial
– Selection of plant variant
– Allows for evolution to occur

• May be detrimental
– Many heritable diseases are as a result of a mutation in the DNA
– e
...
cystic fibrosis
• A C-to-T change in nucleotide 1609 in exon 10 is responsible for a
stop mutation at position 493 in the CFTR (cystic fibrosis
transmembrane conductance regulator)
...
Natural mutations at low rate
...
Transitions – like with like, purine by purine,
pyrimidine by pyrimidine
b
...
g
...
e
...

– A lot depends on how bad the situation is
• Last ditch attempt to save the cell

System to deal with water damage

• Glycosylase breaks link between uracil (deaminated base) and
ribose-phosphate back bone
• 2 cuts remove Apurinated (AP) sugar (can be Apyrimidated)
–
–
–
–

Endonuclease cuts 5’ to AP site (frees an –OH group)
Exonuclease cuts 3’ to AP site
Gap generated
Filled in by DNA Pol I

DNA Glycosylase constantly
checking DNA
• Several different kinds in
the cell
– Specific to the lesion in
the DNA

• Flips base out to check it
– Energetically not too
expensive

Protein in grey ribbons, DNA in purple stick model, oxoG in red stick
From Bruner etal Nature 2000 Vol 403 pgs 859-866

Getting rid of acylations
• Methyltransferase moves methyl group
from G to a cysteine side chain –SH group
• Methyltransferase can only be used once
– Expensive for the cell

Getting oxoG out

• Early stage: removed by base excision
– DNA glycosylase

• Post replication: have oxoG:A pair
– Fail safe glycosylase system specific for this damage
– Removes the normal A
– System gets a second chance to pull out the oxoG
...
coli
• Involved in UV damage repair
and others
• UvrAB check DNA
• Find lesion
• UvrA leaves
• UvrB melts DNA around lesion
• UvrC binds to UvrB, nicks DNA in
two places, 12-13 bases removed
• DNA pol I and DNA ligase, fill and
join up gap respectively
...
g
...


Translesion DNA synthesis
• A drastic, error prone
recovery
• When cell hasn’t repaired
lesion
• Normal DNA pol III stops,
and dissociates
• Translesion pol binds
• Adds bases across lesion
• Dissociates and DNA pol III
rebinds to finish job
...
Lewin

Back up a minute
• DNA replication stalls on
strand using damaged
template

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