world cancer report - iarc

I
Reactive oxygen species
Methylation, deamination
DNA
glycosylase
APE1
II
DNA polβ
XRCC1
IV
V
DNA
ligase 3
VI
+dGTP
SHORT-PATCH BASE EXCISION REPAIR
(Main pathway)
Fig. 3.11 Stages of base excision repair. Many glycosylases, each of which deals with a relatively narrow
spectrum of lesions, are involved. The glycosylase compresses the DNA backbone to flip the suspect
base out of the DNA helix. Inside the glycosylase, the damaged base is cleaved, producing an “abasic”
site (I). APE1 endonuclease cleaves the DNA strand at the abasic site (II). In the repair of single-stranded
breaks, poly(ADP-ribose)polymerase (PARP) and polynucleotide kinase (PNK) may be involved. In the
“short-patch” pathway, DNA polymerase β fills the single nucleotide gap and the remaining nick is sealed
by DNA ligase 3. The “long-patch” pathway requires the proliferating cell nuclear antigen (PCNA) and
polymerases β, ε and δ fill the gap of 2-10 nucleotides. Flap endonuclease (FEN-1) is required to remove
the flap of DNA containing the damage and the strand is sealed by DNA ligase 3.
cleotide (IV) and the gap is filled in by
PCNA-dependent polymerases (POL)
epsilon and delta and sealed by a DNA ligase,
presumed to be LIG1 (V). Nucleotide
excision repair in regions which are transcribed
(and hence code for proteins)
requires the action of TFIIH [11].
Spontaneous hydrolysis
(abasic site)
DNA
ligase 1
X-rays
(single-stranded break)
XRCC1
FEN1
PCNA
PARP
PNK
III
VII
VIII
IX
DNA base excision repair (Fig. 3.11, steps
I to VI or steps III to IX) involves the
removal of a single base by cleavage of
the sugar-base bond by a damage-specific
DNA glycosylase (e.g. hNth1 or uracil DNA
glycosylase) and incision by an
apurinic/apyrimidinic nuclease (human
P
P
OH
DNA pol δ/ε
+dNTPs
LONG-PATCH BASE EXCISION REPAIR
(Minor pathway)
Fig. 3.12 In the human genome there are
numerous places where short sequences of DNA
are repeated many times. These are called
microsatellites. In DNA from a patient with hereditary
nonpolyposis colorectal cancer, there are
changes in the number of repeats in the
microsatellites. Note the difference in the
microsatellite pattern between normal (N) and
tumour tissue (T) from the same patient. This
microsatellite instability is caused by errors in
post-replicative DNA mismatch repair.
AP1) [12]. Gap-filling may proceed by
replacement of a single base or by resynthesis
of several bases in the damaged
strand (depending on the pathway
employed).
More complex and unusual forms of damage
to DNA, such as double strand breaks,
clustered sites of base damage and noncoding
lesions that block the normal replication
machinery are dealt with by alternative
mechanisms. Inherited human diseases
in which the patient shows extreme
sensitivity to ionizing radiation and altered
processing of strand breaks, such as ataxia
telangiectasia and Nijmegen breakage
syndrome, constitute useful models to
study the repair enzymes involved in these
processes. Indeed, if elucidation of base
excision repair and nucleotide excision
repair was the great achievement of the
late 1990s, then understanding strand
Carcinogen activation and DNA repair 93