5-Repair
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normal DNA replication:
A strand of DNA serves as template for the synthesis of a complementary, antiparallel strand in the 5’ to 3’ direction.
The breaking of the high-energy P-P bond (phosphoanhydride) in the dNTP provides:
the energy required for the formation of the new phosphodiester bond.
DNA polymerase has:
3’ to 5’ exonuclease activity (proofreading).
if a wrong nucleotide is placed during the regular 5’ to 3’ DNA synthesis:
DNA polymerase can remove it (3’ to 5’ exonuclease activity) *the enzyme then replaces it with the correct nucleotide by resuming the 5’ to 3’ polymerase activity.
what makes proof reading possible?
The synthesis of DNA in the 5’ to 3’ direction
during a hypothetical 3’ to 5’ DNA polymerization (right), the energy necessary for the formation of the new phosphodiester bond would come from:
the breaking of the high-energy P-P (phosphoanhydride) bond at the 5’ end of the growing chain
if the last nucleotide (the triphosphate) were removed as part of proofreading:
no high energy bond would be available for the addition of the next nucleotide
The consequence of errors in DNA replication is nucleotide:
mismatches that can lead to permanent changes if they are left unrepaired before the next round of DNA synthesis.
Consequences of errors in DNA replication:
Proofreading failed: C => A mutation, Permanent G => T substitution
Incorrect mismatch repair:
G => T in the template strand
Correct mismatch repair:
A => C in the new strand
Consequence of a point mutation in the B-globin gene:
sickle cell anemia
Sickle-cell anemia is caused by a:
single nucleotide substitution in the DNA. The resulting amino acid change alters the tertiary structure of B-globin.
Proofreading fails:
a wrong nucleotide is placed by mistake during DNA replication.
how does the cell know which strand is the newly synthesized strand
the recently synthesized strand has breaks (nicks)
strand is interrupted due to discontinuous replication, resulting in:
Okazaki fragments
mismatch repair must be done before
nick repair occurs
Model for mismatch repair in eukaryotes: step one
DNA mismatch repair proteins recognize the mismatched pair (due to the resulting topological disturbance) and bind to it
Model for mismatch repair in eukaryotes: step two
the DNA is scanned for a nearby nick
Model for mismatch repair in eukaryotes: step three
the nicked strand is digested all the way from the nick back to the mismatch site
Model for mismatch repair in eukaryotes: step four
DNA polymerase and DNA ligase complete the repair
Hereditary nonpolyposis colorectal cancer (HNPCC):
*affects ~1 in 200 people *it is caused by defects in the MutS or MutL genes, which code for DNA mismatch repair proteins *results in higher frequency of mutations in other genes, such as those that regulate cell proliferation
spontaneous mutation categories:
*deaminations *radiation-induced dimerizations
spontaneous mutation consequences:
*distorted strands *mismatches that include unusual bases