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