world cancer report - iarc

which remove the mismatched bases, or
long-patch mismatch repair involving
homologues of the bacterial genes MUTS
and MUTL (Fig. 3.13). Insertion or deletion
loops at microsatellite sequences can be
recognized by hMutSα (a heterodimer of
hMSH2 and hMSH6) or hMutSβ (a heterodimer
of hMSH2 and hMSH3).
Subsequent recruitment of hMutLα (a heterodimer
of hMLH1 and hPMS2) to the
altered DNA targets the area for repair,
which requires excision, resynthesis, and
ligation. Single nucleotide mispairing
events require hMutSα function for recognition.
One important requirement of such
repair processes is that they are able to
distinguish the correct base from the
incorrect one in the mispair. Since both
bases are normal constituents of DNA, this
cannot be achieved by an enzyme that
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scans the DNA for a lesion or structure
that is not a normal constituent of the
DNA. Defects in at least four of the genes
whose products are involved in mismatch
repair, namely hMSH2, hMLH1, hPMS1
and hPMS2, have been associated with
hereditary nonpolyposis colorectal cancer.
This is one of the most common genetic
diseases and affects as many as 1 in 200
individuals and may account for 4-13% of
all colorectal cancers (Colorectal cancer,
p198). Affected individuals also develop
tumours of the endometrium, ovary and
other organs. The DNA of hereditary nonpolyposis
colorectal cancer tumours is
characterized by instabilities in simple
mono-, di- and trinucleotide repeats which
are common in the human genome (Fig.
3.12). This instability is also seen in certain
sporadic colorectal tumour cells and arises
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D, Romieu A, Ravanat JL (2000) Oxidative base damage to
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899.
Me
Fig. 3.14 The repair of O 6-methylguanine by
O 6-alkylguanine-DNA-alkyltransferase.
directly from alterations in the proteins
involved in mismatch repair [14]. Generally
speaking, genomic instability is considered
an indicator of, and fundamental to the
nature of, malignant cell growth.
WEBSITES
MGMT
Cys
A comprehensive listing of human DNA repair genes:
http://www.sciencemag.org/cgi/content/abstract/291/
5507/1284
DNA Repair Interest Group (NCI):
http://www.nih.gov:80/sigs/dna-rep/
MGMT
Cys
Me
Carcinogen activation and DNA repair 95