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.
? The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com
by guest on October 27, 2015
complex in NHEJ is still poorly defined, it is known to play a pivotal
role inHR. MRN keepsthe DNAends inclose proximity to each other
(40,41), recruits and activates the Ataxia Telangiectasia mutated pro-
tein kinase, which is a key mediator of the DNA damage response
signaling pathways (42,43), and is required for end resection to gen-
erate the long 3#-ssDNA overhangs (44) required for HR. In yeast, it
has been proposed that the MRX complex (an analog of MRN) to-
gether with Sae2 initiates the resection of the 5#-strand on each side of
a DSB (45). In mammalian cells, the ortholog of Sae2, CtIP, has been
implicated in DSB resection, throughits stimulation of MRN nuclease
activity (46–48). The 3#-ssDNA is rapidly bound by replication pro-
tein A (RPA), and through the action of BRCA1, BRCA2 and PALB2,
the Rad51 protein is recruited and coats this ssDNA segment displac-
ing RPA and forming a RAD51 nucleoprotein filament (49). Error-
free HR repair involves invasion of the RAD51 nucleoprotein filament
into the intact sister chromatid. After strand invasion, a search for
a homologous sequence is initiated (50). Once homology is found,
the invading ssDNA acts as a primer for DNA synthesis by an as yet
unidentified DNA polymerase(s). DNA polymeraseg can perform this
synthesis invitro (51), but whether this occurs invivo has not yet been
determined. Strand invasion results in the displacement of the second
strand of the sister chromatid, thus forming a D-loop structure. In the
classical homologous recombination model (Figure 1b), the displaced
strand from the sister chromatid anneals to the 3#-overhang from the
other end of the DSB. The displaced strand can now act as template
for DNA synthesis primed by this second end of the DSB. Completion
of DNA replication from the 3#-overhangs generates a joint molecule,
with both sister chromatids connected via a double Holliday junction
(dHJ). The dHJ must then be resolved in order to generate an intact
repaired DNA molecule. The exact proteins required for Holliday
junction resolution remain unclear, but recently the GEN1 Holliday
junction resolvase was discovered in human cells (52) and SLX4 has
been shown to play a role in resolution in higher eukaryotes (53–56).
Resolution of dHJs may result in a crossover or non-crossover event.
It should be noted, however, that crossing-over is a rare event during
HR in somatic cells (57–60). While crossing-over is essential for
generation of allelic diversity during meiosis, it may also have nega-
tive consequences. For example, if a mismatched base pair is present
Fig. 1. (a) Upon generation of a DSB, the MRN complex recognizes the lesion. The MRN complex recruits CtIP and BRCA1/BARD1. MRN nuclease activity is
stimulated following its interaction with CtIP. This nuclease activity, together with other unconfirmed factors, generates 3#-ssDNA overhangs on either side of the
break that rapidly bind RPA. Through its interaction with PALB2, BRCA1 leads to the recruitment of BRCA2, which, in turn, recruits and loads the Rad51
recombinase, displacing RPA. This RAD51 nucleoprotein filament catalyzes strand invasion and initiates the homology search on the intact sister chromatid.
(b) Classical HR model. Once homology is established, the invading strand primes DNA synthesis using the sister chromatid as a template. The second
3#-overhang is ‘captured’ by the displaced strand of the sister chromatid, and this also primes DNA synthesis. After repair is complete, the two sister chromatids
are linked by a dHJ. Holliday junction resolving enzymes can resolve this structure in a crossover-generating manner or non-crossover-generating manner.
(c) Synthesis dependent strand annealing. In synthesis dependent strand annealing repair, once DNA synthesis has generated a sequence complementary to the
other side of the DSB, the invading strand is displaced from the sister chromatid and anneals to the opposing 3#-overhang. Gaps are filled in by further DNA
synthesis. Repair can only generate a non-crossover product since the second 3#-end never anneals to the displaced strand of the sister chromatid.
P.J.O’Donovan and D.M.Livingston
by guest on October 27, 2015
on the sister chromatid template then it will generate a mutation inone
of the duplexes during 3#-overhang-initiated DNA synthesis. If the
resulting dHJ is resolved in a crossover manner, this mutation will
become fixed in the repaired chromatid.
An alternative model was proposed to potentially explain the non-
crossover repair bias in HR, namely synthesis-dependent strand an-
nealing (Figure 1c). In the synthesis-dependent strand annealing
model, the initial steps of strand invasion and DNA synthesis from
the invading 3#-strand occurs just as in the classical HR model. How-
ever, there is no capture of the second 3#-overhang by the displaced
sister chromatid strand. Instead, after synthesis from the invading
3#-overhang, the newly synthesized product becomes displaced and
anneals to the processed 3#-overhang on the opposite side of the DSB.
Further DNA synthesis can then fill in the gaps on both strands.
BRCA1 in DSB repair
The BRCA1 gene is located on chromosome 17q21, and its primary
product is a 1863 residue protein (Figure 2a(i)). The BRCA1 protein
(a.k.a. p220) contains a RING domain in its N-terminal region and
a coiled-coil domain together with tandem BRCT repeats in its
C-terminal region. These domains are critical in the known DNA
repair and DNA damage response signaling functions of BRCA1.
BRCA1 is a component of a number of supercomplexes, each of
which plays a role in DNA damage response activation, cell cycle
checkpoint activation and/or DSB repair (all are functions elicited by
DSBs) (Figure 2b). BRCA1 normally exists as a heterodimer with
another RING/BRCT domain-containing protein, BARD1. In the ab-
sence of BARD1, BRCA1 is unstable and is rapidly degraded and vice
versa (61). The interaction between these two proteins is mediated by
alpha-helical units adjacent to their RING domains (62). The RING
domain is highly conserved among BRCA1 and BARD1 gene prod-
ucts of multiple species and is a core component of many E3 ubiquitin
ligases. In vitro, the BRCA1–BARD1 heterodimer serves as an ubiq-
uitin ligase (63–65), although its in vivo, physiological substrates are
as yet largely unknown. This E3 ligase activity is essential for
BRCA1-mediated suppression of genomic instability (64,65). Re-
cently, however, there has been some controversy regarding the
Fig. 2. a(i) DomainorganizationofBRCA1andBRCA2.Sequences thatabut the BRCA1N-terminalRINGdomainarelargely responsibleforits interaction with
BARD1. C-terminal to this domain is a nuclear localization signal. The central part of BRCA1 is devoid of established protein interaction or enzymatic function
domains. Toward the C-terminus, there is a coiled-coil domain that interacts with a coiled-coil domain in PALB2. The C-terminal BRCT repeats are
phosphoprotein interaction domains, responsible for multiple BRCA1/partner protein interactions. a(ii) BRCA2 is a protein of 3418 aa. The N-terminal 40
residues are necessary and sufficient for its interaction with PALB2. The BRC repeats and the TR2 region are required for interactions with RAD51 and its loading
onto ssDNA. The a-helical domain interacts with DMC1 and contributes to BRCA2 function in meiosis. The OB folds bind to ssDNA and are likely involved in
BRCA2 HR function. (b) Schematic of the various protein supercomplexes of which BRCA1 is known to be a major subunit. These structures play a role in
maintaining genomic stability. These complexes do not appear to operate independently of one another but rather cooperate to promote physiological BRCA1 HR
Breast/ovarian cancer susceptibility gene products
by guest on October 27, 2015
involvement of the E3 ligase activity of BRCA1/BARD1 in DSBR. It
was reported that in isogenic mouse ES cells, a BRCA1 mutant lack-
ing its E3 ligase activity demonstrated near wild-type levels of
BRCA1-mediated DNA repair (66). Subsequently, we have demon-
strated that the BRCA1 mutant used in these experiments
(BRCA1I26A) retains some E3 ligase activity (6). This residual activ-
ity may be enough to allow BRCA1 to perform its DSB repair activ-
ities. Clinically relevant mutations occur within the RING domain
that affect the BRCA1–BARD1 E3 activity, and the frequency, la-
tency, histopathology and cytogenetic features of tumors from
BRCA1-, BARD1- or BRCA1-ablated þ BARD1-ablated mouse
mammary glands are similar (67). This implies that the known tumor
suppressor functions of BRCA1 require its interaction with BARD1.
Whether this is due to the known E3 ligase activity of the heterodimer
and/or the role of BARD1 in stabilizing the BRCA1 protein remains
For BRCA1 to carry out its DSBR functions, it must first become
localized to a DSB-containing chromatin site. The BRCT repeats of
BRCA1 are phosphopeptide-binding domains (68) essential for its
targeting to sites of DNA damage (69–72). The Abraxas protein in-
teracts with the BRCT repeats and links BRCA1 with the ubiquitin-
binding protein RAP80. RAP80 contains two ubiquitin interacting
motifs, and these bind one or more polyubiquitinated proteins at
DSBs, helping to target BRCA1 in a timely manner (73,74). In the
absence of RAP80, BRCA1 is still recruited to sites of damage, but to
a much lesser extent. While one consequence of the absence of
RAP80 or Abraxas is hypersensitivity to ionizing radiation, the phys-
iological basis for this defect has, as yet, not been reported.
As briefly mentioned above, BRCA1 plays a major role in DSB
repair by HR. After induction of DSBs by ionizing radiation, BRCA1/
BARD1 heterodimers form a number of distinct protein supercom-
plexes with a variety of different binding partners. One of these com-
plexes consists of BRCA1, CtIP and the MRN complex (47,75–77).
As described above, it is thought that CtIP and the MRN complex
function together in the generation of ssDNA at DSB ends. Depletion
of CtIP leads to a marked reduction in ssDNA generation and RPA
foci formation at DSBs. The BRCA1 interaction with CtIP only oc-
curs after CtIP becomes phosphorylated in the S- and G2-phases of the
cell cycle, when HR is the prominent form of DSBR (78). In addition,
the BRCA1 interaction with MRN components can be enhanced by
genotoxic stress, and BRCA1 is itself required for efficient generation
of ssDNA at DSBs, although whether this is a direct or indirect func-
tion of the protein is unclear (76,79). In this regard, in chicken DT40
cells, it was demonstrated that expression of a CtIP mutant, unable
to be phosphorylated, and, thus unable to interact with BRCA1, led
to a decreased level of ssDNA generation after DSB induction (47).
However, CtIP still interacts with MRN in the presence of a mutant
BRCA1 species that cannot interact with CtIP (46). Taken together,
these data suggest that a direct role for BRCA1 in end resection is
possible but has yet to be definitively shown.
In addition to a possible role in 5#-end resection, BRCA1 is also
involved in a later stage of HR. This role is dependent on the inter-
action between BRCA1 and BRCA2 (80), which is necessary for the
recruitment of RAD51 (77,81,82) and generation of the RAD51 nu-
cleoprotein filament that mediates strand invasion. BRCA1 and
BRCA2 interact through a mediator protein, PALB2 (83,84). BRCA1
and PALB2 interact via their respective coiled-coil domains and
mutations in the BRCA1 coiled-coil domain that abolish its PALB2-
binding activity result in compromised HR function (83). These
mutations were found in BRCA1 tumors, implying that loss of this
specific BRCA1 function in DSB repair is one source of the genomic
instability and tumorigenesis observed in this subset of BRCA1
Other genome stability roles for BRCA1
In addition to a direct role in DSB repair, BRCA1 possesses other
functions that promote genome stability and cell survival. Upon gen-
eration of DNA damage, cell cycle checkpoints are activated that
arrest cells and allow them time to repair the damage before progress-
ing. If the damage is not resolved, then the cells can remain arrested
until an apoptotic pathway is activated. In the absence of such check-
point responses, sufficient time may not be afforded for the DSB to be
fully repaired prior to mitotic entry and may lead to genome instabil-
ity, manifest by such abnormal developments as chromosomal loss
and/or missegregation. The BRCA1–RAP80–Abraxas complex de-
scribed above is not only directly involved in DSBR but also in the
G2–M checkpoint (69–72,74).
Through a still unknown mechanism, BRCA1 also regulates
phosphorylation of the CHK1 kinase, a protein known to be in-
volved in DNA damage-driven cell cycle checkpoint control (85).
This regulation correlates with the ability of BRCA1 to accumulate at
damage-induced foci (86–88), although how and why this is so is not
understood. Activated CHK1 is also required for the phosphorylation
of the FANCD2 and FANCE components of the Fanconi anemia (FA)
pathway (89,90), which is involved in the repair of DNA interstrand
cross-links, by a mechanism that, at least in part, involves HR. Thus,
the influence of BRCA1 on CHK1 function might represent another
means by which it contributes to the HR process.
BRCA1 has also been ascribed a role in those replication check-
points that are activated in response to replicative stress such as stalled
or collapsed replication forks (91,92). This appears to be via its in-
teractions with BACH1 and TOPBP1. BACH1 is a helicase and binds
to the BRCA1 BRCT repeats (93). This interaction occurs during
S-phase and requires BACH1 phosphorylation (94). In the absence
ofBACH1 activation,cells fail toprogress throughS-phaseina timely
manner (95). TOPBP1 is known to be involved in DNA replication
and checkpoint control (96,97) and was found to be part of the
BRCA1–BACH1 complex (77). Absence of any of these three pro-
teins results in failure of cells to slow their progression through
S-phase following ionizing radiation. Moreover, all three proteins
are loaded onto replication origins after exposure to DNA-damaging
agents and appear to facilitate the removal of, or prevent the loading
of, the CDC45 origin-licensing factor (77).
The BRCA1/BARD1 heterodimer is also active in mitosis control.
In Xenopus laevis cell-free extracts and human cells, the BRCA1–
BARD1 complex is required for mitotic spindle pole assembly, and
the absence of BRCA1 results in defective spindle pole formation (6).
Defective spindle pole and spindle formation lead to genomic insta-
bility due to incorrect chromosomal segregation, and, thus can result
in aneuploidy, a hallmark of BRCA1 tumors.
Finally, BRCA1 regulates the ubiquitination status of topoisomer-
ase IIa (98), which is involved in the decatenation of sister chromatids
after their replication. Failure to decatenate chromatids can also lead
to aneuploidy, and lagging chromosomes are observed in BRCA1-
deficient cells. Moreover, BRCA1 is also a centrosomal protein and
in that setting may be engaged in the control of centrosome duplica-
tion, which also has the potential to elicit a defect in chromosomal
Therefore, through its ability to participate in error-free DSBR,
checkpoint control, mitotic spindle assembly, sister-chromatid deca-
tenation and centrosomal duplication, BRCA1 plays a critical role
in maintaining genome stability. As such, failure of BRCA1 function
leads to genomic instability by any of several pathways resulting
in gross chromosomal rearrangements, chromosomal missegregation
and aneuploidy. Since many of the mutations identified in BRCA1
families have been demonstrated to affect these BRCA1 functions,
one can surmise that these activities are required for BRCA1 tumor
BRCA2 in DSB repair
The BRCA2 gene (located on chromosome 13q) encodes a protein of
3418 residues (Figure 2a(ii)). Its primary function is in HR and is
based upon its ability to bind to the strand invasion recombinase,
RAD51 (80,101–104). BRCA2 contains eight BRCT repeats, each
of which can bind Rad51, and an ssDNA-binding domain, the exact
role of which remains unclear.Recruitment ofRAD51 to sites of DNA
P.J.O’Donovan and D.M.Livingston
by guest on October 27, 2015
damage requires BRCA2. Given the absolute requirement for RAD51
in HR, its not surprising that BRCA2-deficient cells exhibit genomic
instability (8,105–107). As mentioned above, BRCA2 interacts with
PALB2, through which it localizes to DSBs together with BRCA1.
Once concentrated at a DSB, BRCA2 is able to load RAD51 onto the
3#-ssDNA overhangs, displacing RPA (108,109). After RAD51 load-
ing, BRCA2 functions to stabilize the resulting nucleoprotein fila-
ment, through the TR2 domain at its C-terminus (110). BRCA2
also participates in meiotic recombination through its interaction with
the DMC1 recombinase (111), and in BRCA2-deficient mice, there is
persistence of Spo11-induced DSBs in the gonads (products of the
early steps in meiotic recombination) and such animals are infertile
FA is a rare genetic disorder characterized by a high cancer
incidence and developmental disorders (reviewed extensively in ref.
113). A hallmark of FA cells is their hypersensitivity to DNA cross-
linking agents. Three of the thirteen FA complementation groups re-
sult from mutations in BRCA2, PALB2 and BACH1. It has been
proposed that repair of interstrand DNA cross-links may require
HR, and thus, the role of BRCA2 in FA may be due to its contribution
to HR. It is tempting to ascribe a role for BRCA1 in FA due to the
involvement of multiple BRCA1-interacting proteins in FA disease
prevention, but there is as yet no compelling evidence for such a role.
The known effects of BRCA2 loss on genome stability are also
observed in tumors that arise in BRCA2 mutation carrying families.
As in the case of BRCA1, the gross chromosomal rearrangements and
aneuploidy that develop in BRCA2-deficient cells may also be in-
volved in BRCA2 tumorigenesis. It should be noted here that while
BRCA1 and 2 families both primarily develop breast and ovarian
tumors, the breast tumors are often pathologically distinct form each
other, with most BRCA1 cancers being basal-like, whereas most
BRCA2 tumors are luminal (114–116).
BRCA1 and BRCA2 play a number of major roles in the maintenance
of genome integrity. They are involved directly in a number of steps
during DSBR; they control cell cycle checkpoint responses and they
are involved in chromosomal segregation. Yet, the detailed mecha-
nisms by which these large proteins operate in vivo are still not well
understood. Recently, it has been shown that inactivating TP53BP1,
a major player in NHEJ, could rescue the sensitivity of BRCA1-null
cells to DNA-damaging agents (117), suggesting that, in the absence
of BRCA1 and NHEJ, some form of HR is still able to function and
repair DSBs (A.Nussensweig, personal communication). Such work
illustrates well the complexity of the BRCA1 and 2 damage response,
and the cross talk between various DNA repair and DNA damage
In addition, it has been known for some time that chromatin state
can affect the ability of a cell to repair DNA damage (118,119) and
that the presence of DNA damage affects chromatin state ((118) re-
viewed in ref. 119,120). In this regard, in higher eukaryotes, repair of
DNA DSBs in heterochromatin seems to occur less efficiently in
heterochromatin than in euchromatin (121,122), and wild-type Ataxia
Telangiectasia mutated protein is required for their repair in hetero-
chromatin but not in euchromatin, at least in the G0/G1-phases of the
cell cycle (121,122). Hence, there are different requirements for DSB
repair in heterochromatin and in euchromatin. The fact that BRCA1 is
known to interact with chromatin remodeling proteins in vivo (123)
makes it an attractive protein to study in this regard, and we are
currently trying to learn whether its DSBR function is differentially
directed at DSB in heterochromatin versus euchromatin.
Clinically, the genomic instability phenotype of BRCA1- and
2-deficient cells may provide an opportunity for treatment. Recently
much interest has been generated in poly(adenosine diphosphate-
ribose) polymerase (PARP) inhibitors. PARP1 is involvedin the repair
of DNA single-strand breaks (124,125), and failure of their repair can
lead to the generation of DSBs during DNA replication. Inhibition of
PARP1 is suspected of leading to a large increase in DSBs that, in
the absence of BRCA1 or 2, and hence a proper HR response, cannot
be repaired and are suspected of leading to cell death (126). In HR-
proficient cells, however, these breaks can be efficiently repaired, and
this is hypothesized to suppress their potential lethality. In BRCA1-
and BRCA2-deficient cell lines and in mouse BRCA1 breast cancer
models, inhibition of PARP1 can lead to selective death of tumor cells
(126,127), providing proof of the concept that induction of excessive
DNA damage in repair deficient tumors may provide a novel strategy
for cancer therapy, at least in women with BRCA1 and 2 cancers.
Indeed, in a recent clinical trial, the PARP inhibitor olaparib was dem-
onstrated to exhibit antitumor activity in BRCA1- and 2-associated
cancers while exhibiting side effects far less severe than conventional
While much more is known than was the case a decade ago, it
would be naive to assume that a majority of the mysteries surrounding
BRCA1 and BRCA2 function have been deciphered. In that context,
there may well be much more to learn of the clinical impact of
BRCA1 and BRCA2 misbehavior.
Conflict of Interest Statement: None declared.
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Received February 26, 2010; revised March 24, 2010;
accepted March 24, 2010
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