Biology Reference
In-Depth Information
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FIGURE 7.5
Model of HRR deregulation leading to genomic instability, based on the concept developed by Wiese and Schild.
129
In this
model, any form of HRR deregulation, such as upregulation of RAD51 expression, for example due to loss of p53, or suppressed HRR, for
example due to BRCA1 mutation, will lead to genomic instability. Because some level of adequate HRR is required for cells to proliferate
a second event is required to balance the hyperactive or reduced levels of HRR, respectively. See text for more details.
tumors.
129,226
A weakness of this argument, however,
is that although p53 inactivation rescues the lethality
of Brca1 mutant mice it does so without rescuing HRR,
in contrast to loss of 53BP1. On the other hand, cancers
associated with mutation of MMR genes, which do not
impair HRR, are much less frequently associated with
p53 mutations, which supports the notion that p53 loss
may serve to counteract at least some HRR defects.
129
p53 has been identified as a suppressor of both RAD51
protein function and expression levels. In 1997, Powell
and colleagues observed that human tumor cell lines
displayed 100- to 10,000-fold higher HR rates than
normal fibroblasts.
228
Subsequent studies from several
laboratories have since established that p53 downregu-
lates RAD51 activity in a variety of experimental
settings.
229
e
233
There appear to exist a multitude of
mechanisms by which p53 is able to affect RAD51
activity, including binding to BRCA2, RPA, RAD51,
and HR intermediates.
230,234
e
238
Additionally, p53
downregulates expression of the RAD51 gene through
binding to a p53 response element in the RAD51
promoter.
239
The HR regulatory function of p53 is likely
one means by which p53 maintains genomic stability.
237
Because p53 is mutated in the majority of human
cancers, upregulated HRR may be a common feature
of these tumors.
240
However, a comprehensive analysis
of the effects of common p53 mutations on HR levels
is largely lacking,
229,231
yet would be required for the
interpretation of HR activities in a given tumor. In
particular, whether any of the p53 mutations may confer
a gain-of-function phenotype that is associated with
hyperactive HRR would be of considerable interest.
Based on the available data, it can be hypothesized
that p53 mutation may constitute a frequent mechanism
to counteract genetic or epigenetic disruption of HRR
pathway components in human cancers.
129
For example,
it has been argued that the high incidence of p53 muta-
tions in breast cancers due to BRCA1/2 germ line muta-
tions may reflect the need to rescue HRR in these
Role of 53BP1 in Regulation of RAD51
Recent studies also identified loss of 53BP1 as a mech-
anism that can rescue HRR in BRCA1-deficient cells.
88,89
These data suggest that BRCA1 functions in an early
step of HRR, likely DNA end resection, which requires
removal of 53BP1 from the break site (illustrated in
Figure 7.6
). In the absence of BRCA1, 53BP1 is retained
and blocks resection and subsequent HRR. It was shown
that loss of 53BP1 was frequently found in triple-nega-
tive breast cancers as well as in familial breast cancers
with known BRCA1 mutations.
88
Experimentally, the
HRR levels in BRCA1/53BP1-deficient cells appeared
similar to those seen in wild-type cells.
89
However, it
remains to be determined whether there are settings
where HRR might remain aberrant or whether all repair
functions of BRCA1 are rescued in the double-deficient
tumor cells. For example, recent data fromNussenzweig
and colleagues at the NIH indicate that loss of 53BP1
function actually does not rescue the crosslinker sensi-
tivity of Brca1-deficient cells in a mouse model.
Loss of 53BP1 expression was reported in 43% of
triple-negative breast cancers, which represent only
