DNA damage and repair and their role in carcinogenesis

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DNA damage and repair and their role in
carcinogenesis
Stryer Chapter 28 Lodish Chapter 4.6, 25.5

• A DNA sequence can be changed by copying errors
  introduced by DNA polymerase during replication
  and by environmental agents such as chemical
  mutagens or radiation
• If uncorrected, such changes may interfere with
  the ability of the cell to function
• DNA damage can be repaired by several mechanisms
• All carcinogens cause changes in the DNA sequence
  and thus DNA damage and repair are important
  aspects in the development of cancer
• Prokaryotic and eukaryotic DNA-repair systems are
  analogous

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General types of DNA damage and causes
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Spontaneous C-A base pairing
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Base deamination leads to the formation of a
spontaneous point mutation
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Chemical carcinogens react with DNA and the
carcinogenic effect of a chemical correlates with
its mutagenicity
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Aflatoxin can lead to a modification of guanosine
(in tobacco smoke)
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Mutagens can be tested by their action on
bacteria
His- plates
mutagen
Salmonella test use his mutants deficient in
histidine synthesis (a). Mutagen induces
mutations that restore his (b).
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U
Base excision repair pathway
U
AP
(apurinic/apyrimidinic recognizes missing base)
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Mismatch repair
(likely coupled to replication)
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Thymine-dimer formation
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Thymine-dimers are removed by nucleotide
excision repair
XPXeroderma pigmentosum
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Double-strand breaks occur after ?-irradiation or
replication fork collapse
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Ataxia telangiectasia mutated
Mdm2-P (inactivates Mdm2, which helps to
stabilize p53)
AT patients develop lymphomas and leukemia and
are sensitive to ?-irradiation
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Homologous repair of DSBs via recombination
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Non-homologous end joining (can be error-prone!)
cs
DNA-PK
DNA end resection
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What you need to know DNA damage can occur
spontaneously or through exogenous sources (UV
light, gamma-irradiation, chemotherapeutic
agents) I just want you to know that the
following pathways exist Base excision repair
(e.g., after spontaneous base deamination) Nucleot
ide excision repair (to remove thymine-dimers
after UV) Mismatch repair (defective in
hereditary colon cancer) Double strand break
repair -for homologous repair you need Rad51/52
(homology search and strand invasion) -for
non-homologous end joining you need DNA-PK
(DNA-dependent protein kinase, composed of
Ku86/Ku70 in humans plus the DNA-PK catalytic
subunit (Ku80/Ku70 complex shown in your
handout is yeast homolog). This process is the
preferred DSB repair pathway in humans and it is
often error-prone. ATM is key signaling protein,
senses double-stranded breaks and activates p53,
BUT is not involved in the repair process itself