Carcinogenesis vol.31 no.6 pp.961–967, 2010
Advance Access publication April 16, 2010
BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and
participants in DNA double-strand break repair
Peter J.O’Donovan and David M.Livingston?
Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney
Street, Boston, MA 02115, USA
?To whom correspondence should be addressed. Tel: þ1 617 582 8485;
Fax: þ1 617 632 4381;
BRCA1 and BRCA2 are tumor suppressor genes, familial muta-
tions in which account for ?5% of breast cancer cases in the USA
annually. Germ line mutations in BRCA1 that truncate or inacti-
vate the protein lead to a cumulative risk of breast cancer, by age
70, of up to 80%, whereas the risk of ovarian cancer is 30–40%.
For germ line BRCA2 mutations, the breast cancer cumulative
risk approaches 50%, whereas for ovarian cancers, it is between
10 and 15%. Both BRCA1 and BRCA2 are involved in maintain-
ing genome integrity at least in part by engaging in DNA repair,
cell cycle checkpoint control and even the regulation of key mi-
totic or cell division steps. Unsurprisingly, the complete loss of
function of either protein leads to a dramatic increase in genomic
instability. How they function in maintaining genome integrity
after the onset of DNA damage will be the focus of this review.
BRCA1 and BRCA2 are tumor suppressor genes, familial mutations in
which account for ?5% of breast cancer cases in the USA annually
(1). Germ line mutations in BRCA1 that truncate or inactivate the
protein lead to a cumulative risk of breast cancer, by age 70, of up
to 80%, whereas the risk of ovarian cancer is 30–40%. For germ line
BRCA2 mutations, the breast cancer cumulative risk approaches 50%,
whereas for ovarian cancers, it is between 10 and 15% (2). Like
BRCA1 mutations, which almost exclusively result in female breast
and ovarian cancers, BRCA2 families also show a marked increase in
breast and ovarian cancer. However, unlike BRCA1 families, they
exhibit an increased risk of male breast, pancreas and prostate cancers
(3,4). Tumors of patients from BRCA1 and 2 families typically exhibit
a loss of heterozygosity or other somatic alterations of BRCA1 and 2,
respectively, with the wild-type copy being lost (5). Both BRCA1 and
BRCA2 are involved in maintaining genome integrity at least in part
by engaging in DNA repair, cell cycle checkpoint control and even the
regulation of key mitotic or cell division steps (6). Not surprisingly,
the complete loss of function of either protein leads to a dramatic
increase in genomic instability (7–10). How they function in main-
taining genome integrity after the onset of DNA damage will be the
focus of this review.
DNA double-strand break repair
The eukaryotic genome is under constant stress, one result of which is
the constant generation of DNA damage (11). DNA damage can result
from both endogenous (e.g. reactive oxygen species and cytosine de-
amination) and exogenous (e.g. ultraviolet radiation, ionizing radia-
tion and chemicals) sources. One of the most toxic DNA lesions to
a cell is the DNA double-strand break (DSB). This is because it affects
both strands of the duplex, thus no intact complimentary strand is
available as a template for repair (12). DSBs normally occur during
DNA replication, during the generation of antibody diversity and in
meiosis. DSBs can be induced exogenously by agents such as ionizing
and ultraviolet radiation (reviewed in ref. 13). Failure to repair a DSB
can result in apoptosis, whereas misrepair may lead to mutations or
gross chromosomal rearrangements such as translocations and dele-
tions. Repeated instances of these alterations can over time promote
carcinogenesis and a number of genes involvedin double-strand break
repair (DSBR) are known tumor suppressors (reviewed in ref. 14). In
order to prevent such pathological outcomes, cells have evolved two
major pathways for the repair of DSBs: non-homologous end-joining
(NHEJ) and homologous recombination (HR) (reviewed in ref. 15).
NHEJ involves the direct religation of the ends of a DSB. It is
highly efficient and is the primary DSB repair mechanism used in
the G0-, G1- and early S-phases of the cell cycle (16,17). Upon gen-
eration of a DSB, a Ku70/Ku80 heterodimer is recruited to the DSB
ends (18,19). The Ku heterodimer then recruits DNA-dependent pro-
tein kinase, catalytic subunit (DNA-PKcs) (20–22) and, together with
the DNA ends, activates the DNA-PKcskinase activity, which is re-
quired for its DNA repair function (21). DNA-PKcsmolecules on
either side of the break interact, thus linking both ends (23). The
MRN complex (Mre11–Rad50–Nbs1) was recently demonstrated to
be involved in these early steps of NHEJ (24–26). DSB ends may
require some processing in order for repair to be possible, due to the
presence of damaged bases, and the Artemis protein is recruited to
a DSB following its interaction with DNA-PKcs, to perform this role
(27). Artemis itself exhibits both a DNA-PKcs-independent 5#-to-3#-
exonuclease activity and a DNA-PKcs-dependent endonuclease activ-
ity toward hairpins and double-stranded to single-stranded DNA
transitions (28,29). In the absence of Artemis, cells exhibit radiosen-
sitivity, but do not have a major DSB repair defect, suggesting that not
all DSBs need processing by Artemis to be repaired (30). The
processing of complex lesions at the ends of a DSB may result in
asymmetric termini that need to be religated. Such termini may con-
tain gaps that need to be filled in, and the X-family of DNA poly-
merases (such as Poll, Polk and tdT) are involved in this (reviewed in
ref. 31). The final step in NHEJ involves the religation of the DNA
ends by DNA ligase IV, which is recruited in a complex with X-ray
repair complementing defective repair in Chinese hamster cells 4
(XRCC4) and XRCC4-like factor (32,33).
NHEJ can be error-free or error-prone depending on the nature of
the sequence at a DSB, because the termini at some but not all DSBs
are processed before ligation, and removal of bases can result in loss
of DNA sequence at the break. An alternative end-joining pathway
has been described which can function in the absence of factors in-
cluding Ku, XRCC4 and DNA ligase IV (34–37). Such repair fre-
quently relies upon short regions of homology (microhomology) and
results in small deletions. This error-prone microhomology-mediated
end-joining is not the only form of alternative end-joining, however,
since in the absence of XRCC4–DNA ligase IV, error-free end-joining
can still take place (38).
The second major pathway for DSB repair is HR, generally re-
garded as being error-free (Figure 1). HR relies on the presence of
an intact sister chromatid to act as template for correct repair of the
break without loss of sequence information. As such, HR can only
take place in the S- and G2-phases of the cell cycle. After DSB
recognition by the MRN complex (39), 3#-overhanging single-
stranded DNA (ssDNA) is generated. While the role of the MRN
Abbreviations: dHJ, double Holiday junction; DNA-PKcs, DNA-dependent
protein kinase, catalytic subunit; DSB, double-strand break; DSBR, double-
strand break repair; FA, Fanconi anemia; HR, homologous recombination;
NHEJ, non-homologous end-joining; PARP, poly(adenosine diphosphate-
ribose) polymerase; RPA, replication protein A; ssDNA, single-stranded
DNA; XRCC4, X-ray repair complementing defective repair in Chinese
hamster cells 4.
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Received February 26, 2010; revised March 24, 2010;
accepted March 24, 2010
Breast/ovarian cancer susceptibility gene products
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