world cancer report - iarc

Regulation of the cell cycle and control
of genetic stability
During the cell cycle, a number of potential
problems may result in damage to the
genome. These problems may arise at
three distinct stages: (1) during DNA replication,
especially if the cell is under conditions
of stress that favour the formation of
DNA damage (irradiation, exposure to carcinogens
etc.), (2) following the termination
of DNA replication, when the cell effectively
“switches off” its DNA synthesis machinery
and (3) during M phase, when the cell
has to negotiate the delicate task of segregating
chromatids equally. A tight coupling
between these processes and cell cycle
regulation is therefore crucial to allow the
cell to pause during the cell cycle in order
to afford the time necessary for the successful
completion of all the operations of
DNA and chromosome maintenance.
Failure to do this may result in both genetic
and genomic instabilities, which are hallmarks
of cancer. Genetic instability is characterized
by an increased rate of gene
mutation, deletion or recombination
(essentially due to defects in DNA repair).
Genomic instability results in chromosome
translocations, loss or duplication of large
chromosome fragments and aberrant chromosome
numbers (aneuploidy).
Tens of molecules have been identified as
components of the signalling cascades
which couple detection of DNA damage
and regulation of the cell cycle. One of
these is the product of the tumour suppressor
gene p53 (Oncogenes and tumour
suppressor genes, p96). p53 is specifically
activated after various forms of direct DNA
damage (such as single or double strand
breaks in DNA) and regulates the transcription
of several inhibitors of cell cycle progression,
particularly at the G1/S and
G2/M transitions [7]. Other important molecules
in this coupling process include the
checkpoint kinases chk1 and chk2. Chk1 is
activated after replication blockage during
S-phase. In turn, chk1 activates wee1 and
mik1, two kinases that counteract the
action of cdc25 and keep cdk1 in an inactive
form. Thus, through activation of chk1,
the cell triggers an emergency mechanism
that ensures that cells with incompletely
replicated DNA cannot enter mitosis.
Fig. 3.28 Progression from G1 to S phase is regulated by phosphorylation of the retinoblastoma protein
(pRb), in the absence of which DNA replication cannot proceed.
The cell cycle and cancer
Genes involved in cell cycle control are
important among those subject to the
genetic alterations that give rise to cancer
[8]. However, the proliferation of cancer
cells requires that the cells retain
functional cell cycle processes. The cell
cycle alterations seen in cancer are mainly
confined to two major sets of regulators:
those involved in the negative control
of cell cycle progression (inactivation
of which leads to accelerated and
unchecked cell proliferation) and those
involved in coupling the maintenance of
genome integrity to the cell cycle (inactivation
of which results in cells having
gene alterations that progressively accumulate
during carcinogenesis) (Table 3.3)
[9]. Most of the genes corresponding to
these two categories fall within the group
of tumour suppressors, and many of them
are also direct participants in DNA repair
processes.
The gene which encodes p16 (CDKN2A/
INK4A) has been established as a tumour
suppressor gene [10], and mutations and
deletions at this site are commonly found
in primary human tumours, especially
melanoma (although the contribution of
another protein encoded by the same
locus on chromosome 9p, p14 ARF, to sup-
pressor activity remains to be determined).
Unlike the CDKN2A/INK4A gene,
the CDKN1A gene (encoding p21) is rarely
disrupted in cancer. As p21 plays many
roles in the negative regulation of almost
all phases of the cell cycle, loss of this
function might be expected to result in
uncontrolled cell division. This is apparently
not the case, as mice lacking the
CDKN1A gene do not show an increased
frequency of cancer. This observation
illustrates one of the most important characteristics
of cell cycle regulatory mechanisms:
there is a large degree of redundancy
and overlap in the function of any
particular effector. Therefore, cancercausing
deregulation of the cell cycle
requires a combination of many alterations
in genes encoding proteins that,
either alone or in concert, are critical for
the control of cell division.
Apart from inactivation of negative regulators,
a few cell cycle genes may be activated
as oncogenes, in that their alteration
results in enhanced activity leading
to accelerated cell proliferation. The best
example of such a cell cycle oncogene is
CCND1, the gene encoding cyclin D1, a
G1-specific cyclin [11]. This gene is located
on chromosome 11p13, within a large
region that is amplified in up to 20% of
The cell cycle 107