world cancer report - iarc

SINGLE BASE MISPAIRS INSERTION OR DELETION LOOPS
hMSH6
hMSH2
hMutSα
CTAGGTTA
GATCCGAT
hMSH2
hMLH1
CTAGGCTA
GATCCGAT
hPMS2
hPMS2
hMLH1
Fig. 3.13 Mismatch repair pathways: after DNA synthesis, base pairing mistakes that have escaped the
editing function of DNA polymerase are recognized by mismatch repair proteins.
break repair will probably be the great
achievement of the next decade. This will
have important consequences. Certain
cancers are often treated with radiotherapy
(Radiotherapy, p277) and a small percentage
of patients show considerable
sensitivity to their treatment, with the
result that treatment schedules are
94 Mechanisms of tumour development
hMutLα hMutSα
or hMutSβ
hMSH6
hMSH2
hMSH6
hMSH2
reduced to try to avoid adverse reactions.
A better understanding of the possible
causes of this radiosensitivity, including
characterization of the enzymes involved
in the repair of DNA damage produced by
ionizing radiation, may lead to better tailoring
of radiotherapy doses to individual
patients.
Table 3.2 Spectra of p53 mutations caused by environmental carcinogens or endogenous mechanisms.
Other repair pathways
Human cells, in common with other
eukaryotic and prokaryotic cells, can also
perform one very specific form of damage
reversal, the conversion of the methylated
adduct, O 6-methylguanine, in DNA back to
the normal base (Fig. 3.14). O 6-Methylguanine
is a miscoding lesion: both RNA and
DNA polymerases “read” it incorrectly
when they transcribe or replicate a DNA
template containing it. As this modified
base can pair with both the base cytosine
(its correct partner) and the base thymine
(an incorrect partner), its presence in DNA
can give rise to transition mutations by
mispairing of relevant bases. A specific
protein, O 6-alkylguanine-DNA-alkyltransferase,
catalyses transfer of the methyl
group from the guanine base to a cysteine
amino acid residue located at the active
site of the protein [13]. This error-free
process restores the DNA to its original
state but results in the inactivation of the
repair protein. Consequently, repair can be
saturated when cells are exposed to high
doses of alkylating agents and synthesis of
the transferase protein is required before
repair can continue.
Mismatched bases in DNA arising from
errors in DNA replication, for instance guanine
paired with thymine rather than cytosine,
are repaired by several pathways
involving either specific glycosylases,
Agent Mutation hotspot Type of mutation Tumours associated
(> = changes to)
Benzo[a]pyrene Codons 157, 158, 248, 273 G>T transversions Lung, larynx
(tobacco smoke)
4-Aminobiphenyl Codons 280, 285 G>C transversions Bladder
(aromatic dyes, tobacco smoke) G>A transitions
CA
CACACACA
GTGTGTGT
Aflatoxin B 1 Codon 249 AGG>AGT Hepatocellular carcinoma
(arginine > serine)
Ultraviolet (UV) Codons 177-179, 278 C>T transitions Skin cancer
CC>TT transitions (not melanoma)
Vinyl chloride Several codons A>T transversions Angiosarcoma of the liver
Endogenous mechanism Codons 175, 248, 273, 282 C>T transitions Colon, stomach
(enhanced by nitric oxide) at CpG dinucleotides Brain cancers
hPMS2
hMLH1
CACACACA
GTGTGTGT
hPMS2
hMLH1
hMutLα