world cancer report - iarc

nucleotides may be removed and
replaced before their presence in a DNA
strand at the time of replication leads to
the generation of mutations [9].
Restoration of normal DNA structure is
achieved in human cells by one of several
DNA repair enzymes that cut out the
damaged or inappropriate bases and
replace them with the normal nucleotide
sequence. This type of cellular response
is referred to as “excision repair” and
there are two major repair pathways
which function in this manner: “base excision
repair” which works mainly on modifications
caused by endogenous agents
and “nucleotide excision repair” which
removes lesions caused by environmental
mutagens. UV light is probably the most
common exogenous mutagen to which
human cells are exposed and the importance
of the nucleotide excision repair
pathway in protecting against UV-induced
carcinogenesis is clearly demonstrated in
the inherited disorder xeroderma pigmentosum.
Individuals who have this disease
lack one of the enzymes involved in
nucleotide excision repair and have a
1,000 times greater risk of developing skin
cancer following exposure to sunlight than
normal individuals. The genes in question
have been named XPA, XPB, etc. [10].
One of the great achievements of the last
two decades has been the isolation and
characterization of the genes, and their
protein products, involved in base excision
repair and nucleotide excision repair. It
has become apparent that certain proteins
so identified are not exclusively
involved in DNA repair but play an integral
part in other cellular processes such as
DNA replication and recombination.
Excision repair
The first step in both base excision repair
and nucleotide excision repair is the
recognition of a modification in DNA by
enzymes that detect either specific forms
of damage or a distortion in the DNA
helix. Recognition of damage is followed
by an excision step in which DNA containing
the modified nucleotide is
removed. Gap-filling DNA synthesis and
ligation of the free ends complete the
repair process.
92 Mechanisms of tumour development
Fig. 3.10 Nucleotide excision repair (NER). Two NER pathways are predominant for removal of UV lightand
carcinogen-damaged DNA. In global genome NER, the lesion is recognized by the proteins XPC and
hHR23B while in transcription-coupled NER of protein-coding genes, the lesion is recognized when it
stalls RNA polymerase II. Following recognition, both pathways are similar. The XPB and XPD helicases
of the multi-subunit transcription factor TFIIH unwind DNA around the lesion (II). Single-stranded binding
protein RPA stabilizes the intermediate structure (III). XPG and ERCC1-XPF cleave the borders of the damaged
strand, generating a 24-32 base oligonucleotide containing the lesion (IV). The DNA replication
machinery then fills in the gap (V).
Nucleotide excision repair may occur in
the non-transcribed (non-protein-coding)
regions of DNA (Fig. 3.10, steps I to V). A
distortion in DNA is recognized, probably
by the XPC-hHR23B protein (I). An open
bubble structure is then formed around
the lesion in a reaction that uses the ATPdependent
helicase activities of XPB and
XPD (two of the subunits of TFIIH) and
also involves XPA and RPA (II-III). The
XPG and ERCC1-XPF nucleases excise
and release a 24- to 32-residue oligonu-