STATE-OF-THE-ART REVIEW

BRCA1, a ‘complex’ protein involved in the maintenance

of genomic stability
Kienan I. Savage and D. Paul Harkin
Centre for Cancer Research and Cell Biology, Queen’s University Belfast, UK

Keywords BRCA1 is a major breast and ovarian cancer susceptibility gene, with
BRCA1, breast cancer, DNA repair, DNA mutations in this gene predisposing women to a very high risk of develop-
damage response, hereditary breast cancer,
ing breast and ovarian tumours. BRCA1 primarily functions to maintain
genomic instability
genomic stability via critical roles in DNA repair, cell cycle checkpoint
Correspondence control, transcriptional regulation, apoptosis and mRNA splicing. As a
K. I. Savage, Centre for Cancer Research result, BRCA1 mutations often result in defective DNA repair, genomic
and Cell Biology, Queen’s University instability and sensitivity to DNA damaging agents. BRCA1 carries out
Belfast, Belfast BT9 7BL, UK these different functions through its ability to interact, and form complexes
Fax: +44 (0)289 0972776 with, a vast array of proteins involved in multiple cellular processes, all of
Tel: +44 (0)289 0972760
which are considered to contribute to its function as a tumour suppressor.
E-mail: [Link]@[Link]
This review discusses and highlights recent research into the functions of
(Received 18 September 2014, revised 10 BRCA1-related protein complexes and their roles in maintaining genomic
November 2014, accepted 13 November stability and tumour suppression.
2014)

doi:10.1111/febs.13150

Introduction
Approximately 10% of women diagnosed with breast cancer of up to 20–40% [3]. Additionally, although
cancer report a strong family history, prompting the BRCA1/2 mutations account for a relatively low
search for breast cancer susceptibility genes. In 1994, proportion of breast cancer cases as a whole, it has
the first breast and ovarian cancer susceptibility gene, been found that between 50% and 70% of sporadic
BRCA1, was identified and cloned, followed closely by breast tumours have lost at least one BRCA1 allele,
the discovery of BRCA2 in 1995 [1,2]. To date, over suggesting that the loss of BRCA1 may also be impor-
800 distinct and clinically relevant mutations have tant for sporadic breast cancer development [4]. In
been identified within the BRCA1 gene and, taken addition, hypermethylation of BRCA1 promoters and
together, mutations within BRCA1 and BRCA2 may loss of BRCA1 transcript has also been found in a sig-
account for up to 20% of inherited breast cancer nificant proportion of sporadic breast and ovarian
cases. Moreover, carriers of mutations within BRCA1 tumours [5].
or BRCA2 have a life time risk of developing breast The most striking phenotype of BRCA1 deficient
cancer of up to 60–80% and a lifetime risk of ovarian cells is severe genomic instability and sensitivity to

Abbreviations
AI, aromatase inhibitor; BARD1, BRCA1 associated RING domain protein 1; BRCT, BRCA1 C-terminal; DSB, double-strand break; ERa,
estrogen receptor-a; HR, homologous recombination; ICL, interstrand cross-link; IR, ionizing radiation; MEF, mouse embryonic fibroblast;
NER, nucleotide excision repair; NF-jB, nuclear factor-kappa B; NHEJ, nonhomologous end joining; PARP, poly ADP ribose polymerase;
PARylated, poly(ADP-ribosylated); RPA, replication protein A; SERM, selective estrogen receptor modulator; SSB, single-strand break;
ssDNA, single-stranded DNA; c-H2AX, phosphorylated H2AX.

630 FEBS Journal 282 (2015) 630–646 ª 2014 FEBS

K. I. Savage and D. P. Harkin BRCA1 and maintenance of genomic stability

genotoxic agents, with BRCA1 deficient cells often translational modification mechanism to regulate
exhibiting chromosomal translocations incorporating target protein function and/or recruitment, rather than
large deletions and/or amplifications that involve mul- signaling protein degradation. Although the ubiquitin
tiple, nonhomologous chromosomes [6]. ligase function if BRCA1 is well accepted, its biologi-
Subsequent to its identification, much attention has cal relevance with respect to the tumour suppressor
been focused on understanding the function of BRCA1, function of BRCA1 remains controversial. A recent
with roles identified in multiple cellular processes report suggests that BRCA1/BARD1-mediated ubiqui-
required for maintaining genomic integrity, including tination of histone H2A within heterochromatic
DNA damage signaling, DNA repair, cell cycle regula- regions leads to the repression of satellite DNA, which
tion, protein ubiquitination, chromatin remodeling, suppresses genomic instability [10]. It was demon-
transcriptional regulation, mRNA splicing and apopto- strated that expression of the E3 ligase dead I26A
sis. Although the exact mechanistic role of BRCA1 in mutant of BRCA1 lead to a loss of H2A ubiquitina-
many of these processes remains to be defined, it is tion, de-repression of satellite DNA and genomic
considered that BRCA1 carries out these diverse roles instability. Intriguingly, the I26A mutant is a synthetic
through its ability to interact with a wide range of dif- mutant that does not occur naturally in high-risk
ferent proteins. Indeed, to date, over 100 distinct breast/ovarian cancer families. In addition, the I26A
BRCA1 interacting proteins have been reported and it mutation, although resulting in deficient E3 ligase
is assumed that, through these interactions, the ability function, does not abrogate the interaction between
of BRCA1 to act as a scaffold for the formation of BRCA1 and BARD1. Moreover, mice homozygous
multiple different protein complexes with different for the I26A BRCA1 mutation develop tumours at a
cellular functions underlies its role in a diverse array of similar frequency to BRCA1 wild-type mice and
cellular processes. The remainder of this review will appear to have normal DNA repair capacity, suggest-
focus on the role of BRCA1 within these complexes ing that perhaps, at least in mice, the E3 ligase func-
and their functions, which contribute to the mainte- tion of BRCA1 is dispensable for tumour suppression
nance of genomic stability and carcinogenesis. [11]. By contrast, mice harbouring the pathogenic
C61G mutation, which has been suggested to disrupt
both the E3 ligase function of BRCA1 and the interac-
Structural features of BRCA1
tion between BRCA1 and BARD1, display embryonic
BRCA1 is located on chromosome 17q21.3, spans lethality, DNA repair deficiency and cancer predisposi-
approximately 80 kb of genomic DNA, and is com- tion, although their cells are less sensitive to DNA
posed of 24 coding exons [1]. The BRCA1 gene encodes damaging agents [12]. Taken together, these two stud-
an 1863 amino acid protein, which shares limited ies suggest that the interaction with BARD1 may be
homology with other known proteins but does contain more important than the E3 ligase activity of BRCA1
two functional domains. At its N-terminus, BRCA1 in terms of tumour suppression and DNA repair activ-
contains a series of eight conserved Cys3-His-Cys4 ity. Nevertheless, studies investigating the role of
motif repeats known as the RING domain, a catalytic BRCA1 in ubiquitination at sites of DNA damage in
domain involved in protein ubiquitination and protein– human cells have shown that decreased BRCA1 E3
protein interactions [7]. The most well characterized ligase activity is associated with defective DNA repair.
RING domain interaction occurs with the BRCA1 Indeed, after DNA damage BRCA1/BARD1 mediates
associated RING domain protein 1 (BARD1), forming the ubiquitination of histone H2A (and perhaps other
the BRCA1/BARD1 heterodimer, a known E3 ubiqu- substrates), with the E3-ligase activity of BRCA1/
itin ligase complex [8]. It is now well accepted that BARD1 dramatically increased at double-strand
BRCA1 and BARD1 are obligate heterodimers, with breaks (DSBs) by PIAS1/4-dependent sumoylation of
each protein required for the stability of the other [9]. BRCA1. Intriguingly, depletion of PIAS1/4 results in
The BRCA1/BARD1 heterodimer has been shown defective DSB repair and sensitivity to DNA damaging
to ubiquitinate a plethora of substrates in vitro; how- agents, suggesting that BRCA1-dependent ubiquitina-
ever, the identification of bona fide in vivo substrates tion at DSB sites, which is dependent on PIAS1/4, is
has remained challenging. Nevertheless, several prom- important for DSB repair and may play a role in
ising candidate ubiquitination targets have been sug- tumour suppression.
gested, including the histone proteins H2A, H2B, H3 The C-terminus of BRCA1 contains two conserved
and H4, CtIP, NPM1, RPB8, TFIIE and BRCA1 itself BRCA1 C-terminal (BRCT) domains. These domains
[9]. Interestingly, BRCA1/BARD1 is considered to contain distinct hydrophobic/acidic patches and have
primarily mediate K6-linked ubiquitination as a post- been shown to have transactivation activity [13,14].

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BRCA1 and maintenance of genomic stability K. I. Savage and D. P. Harkin

Subsequent to their discovery within the BRCA1 and therefore only a brief overview of the salient
protein, BRCT domains have been found in many points of these pathways is provided here.
proteins involved in the DNA damage response, such NHEJ is initiated by binding of the Ku70/80 hetero-
as MDC1 and 53BP1, and have more recently been dimer directly to broken double-stranded DNA ends.
described as phosphospecific protein interaction motifs Ku70/80 then recruits the catalytic subunit of the
[15,16]. Not unexpectedly, a number of cancer predis- DNA-dependent protein kinase, thus creating the
posing mutations have also been found within the DNA-dependent protein kinase holoenzyme. Broken
BRCT domains of BRCA1 that affect both the trans- ends are then processed by DNA polynucleotide
activation activity of BRCA1 (discussed below) and its kinase and any latent gaps are filled by DNA polymer-
phosphospecific interaction with other proteins [9]. ase-l. Processed ends are then ligated by the XRCC4–
BRCA1 also contains two nuclear localization sig- ligase IV complex. This process is relatively simple for
nals at amino acids 503–509 and 606–615, respectively, the repair of blunt-ended DSBs. However, for complex
which target BRCA1 to the nucleus [17]. In addition, or ‘ragged’ DBSs, additional proteins are required.
a nuclear export signal at amino acids 81–99 is This process requires the ATM- and MRN-dependent
involved in nuclear cytoplasmic shuttling [18]. activation of Artemis, a nuclease required for addi-
The central region of the BRCA1 protein is largely tional processing of complex breaks. After processing
encoded by a single exon (exon 11) that is present in of ragged DSB ends by artemis, the core NHEJ pro-
vertebrates but not in lower eukaryotes. This region, cess above is used to ligate DNA ends together. NHEJ
covering amino acids 170–1649 contains no known is a rapid DSB repair mechanism and, in the case of
domain structures and is predicted to be intrinsically localized simple breaks, can promote efficient DSB
disordered by both in silico and experimental analysis repair. However, as a result of the nature of this direct
[19,20]. This type of protein structure (i.e. a disordered end ligation process, NHEJ can often result in small
region flanked by structural domains) is typical of scaf- deletions (especially in the case of complex DSBs) and/
fold or ‘hub’ proteins. Disordered regions allow binding or chromosomal rearrangements, thereby contributing
promiscuity as well as structural flexibility between greatly to genomic instability.
ordered domains, thereby facilitating binding diversity By contrast, HR utilizes an undamaged sister chro-
and allowing the conformational flexibility to facilitate matid as a repair template to restore any damaged/lost
the formation of multiple different macromolecular sequence information at the DSB site. Firstly the 50
complexes [20]. Indeed, this region of BRCA1 has been ends of the broken DSB ends are resected, generating
shown to interact with numerous different proteins and a 30 single-stranded region of DNA on either side of
contains a number of DNA damage-induced phosphor- the DSB. This single-stranded DNA (ssDNA) is rap-
ylation sites that are considered to mediate the forma- idly bound by replication protein A (RPA), which pre-
tion of various BRCA1 protein complexes [7]. vents the formation of secondary DNA structures
during resection. RPA is then displaced by Rad51,
which is loaded onto RPA-coated ssDNA in a Rad54,
BRCA1 complexes involved in DNA
PALB2, BRCA2-dependent process. Rad51 loading
repair and cell cycle arrest
then promotes sister strand invasion, generating a het-
DNA damage can arise as a consequence of different eroduplex molecule known as a Holliday junction.
endogenous or exogenous events that are capable of Also required for this process are the structural main-
causing many different types of damage, such as loss, tenance of chromosomes proteins 1, 3, 5 and 6. These
alkylation or oxidation of bases; apurinic/apyrimidinic proteins, also known as cohesins, physically tether the
sites; DNA single-strand breaks (SSBs) and DNA sister chromatids together, stabilizing strand invasion
DSBs. The most hazardous type of DNA damage is and facilitating HR-mediated repair. DNA replication
the DSB. Because broken DNA ends are able to disso- then ensues using the undamaged chromatid as a tem-
ciate, DSBs are not only more difficult to repair, but plate. The Holliday junction is then resolved and the
allow for the re-joining of unrelated ends, thus allow- DNA ends ligated together, resulting in either cross-
ing for gross loss or amplification of genomic informa- over or noncross-over products depending on the
tion, as well as chromosomal rearrangements, all of direction of junction resolution [22].
which are a common feature of BRCA1 loss/deficiency Because HR requires a sister template for repair,
[21]. DSBs can be repaired through two major path- this pathway is only available during S/G2 phases of
ways: nonhomologous end joining (NHEJ) and homol- the cell cycle. Consequently, NHEJ is the predominate
ogous recombination (HR). Both DSB repair repair pathway in G0/G1 cells. However, many DNA
pathways have been extensively reviewed elsewhere damaging agents cause replication-specific DNA dam-

632 FEBS Journal 282 (2015) 630–646 ª 2014 FEBS

K. I. Savage and D. P. Harkin BRCA1 and maintenance of genomic stability

age and/or replication fork stalling. HR plays a major contrast to the CtIP S327A mutant mice, mice
role in the recovery of stalled replication forks where harbouring the CtIP T847A mutation (which is essen-
HR can be activated by accumulated ssDNA at the tial for end resection but does not affect the BRCA1
stalled fork (and subsequent RPA accumulation) or a interaction) had elevated levels of spontaneous chro-
by one-sided DSB formed by a collapsed fork [21]. mosomal aberrations, as well as decreased levels of
The role of BRCA1 in NHEJ, if any, remains ionizing radiation (IR)-induced Rad51 foci, indicating
unclear. BRCA1 has been reported to interact with that CtIP functions independently of BRCA1 to pro-
Ku80 and has been reported to bind DSB sites in a mote end resection. Nevertheless, further investigation
Ku80-dependent manner, suggesting a role for BRCA1 of the role of the BRCA1–CtIP interaction in end
in this pathway [23]. Additionally, NHEJ defects have resection using a high resolution technique (i.e. single
been reported in BRCA1 null mouse embryonic fibro- molecule analysis of resection tracks) allowing visuali-
blasts (MEFs) [24,25]. However, contrasting results zation of the length of the resected DNA in a single
have been reported by other groups, where BRCA1 molecule has shown that, although BRCA1–CtIP is
deficient embryonic stem cells exhibited decreased lev- expendable for the initiation of end resection, disrup-
els of homologous recombination and an increased fre- tion of this interaction decreases the length and speed
quency of NHEJ compared to BRCA1 wild-type of resected DNA generated after DNA damage [33].
parental lines [26,27]. Differences in these results might Therefore, although BRCA1 is not essential for CtIP-
be explained by the use of distinct host cells (embry- mediated end resection, it appears as though interac-
onic stem cells versus MEFs) and BRCA1 mutations tion of BRCA1 with CtIP and within the BRCA1–C
(BRCA1 isoform missing exon 11 versus BRCA1D5–6, complex facilitates the efficiency of this process.
which disrupts all BRCA1 isoforms). As a result, the The exact function of CtIP and BRCA1 within this
exact role of BRCA1, if any, in NHEJ remains uncer- complex and how they biochemically regulate end
tain. resection remains unclear. However, clarification was
By contrast, a number of roles for BRCA in HR- provided in a seminal study by Bunting et al. [34],
mediated DSB repair have been well described, where which found that homologous recombination is
BRCA1 exerts its effects through participation in at completely restored in BRCA1 deficient cells by the co-
least four distinct protein complexes. The BRCA1–C depletion/deletion of 53BP1. 53BP1, an NHEJ promot-
complex consisting of BRCA1, Mre11:Rad50:Nbs1 ing protein, has subsequently been shown to block HR
(collectively known as the MRN complex) and CtIP and promote the NHEJ-mediated repair of DSBs by
plays a role in DSB end resection, a process that also recruiting a number of other pro-NHEJ proteins,
involves EXO1 and DNA2 (Fig. 1) [28]. Initially, the including RIF1 and PTIP [34,35]. BRCA1 and CtIP
BRCA1–C complex was considered to play a role in have been shown to block DSB recruitment of RIF1,
the initiation of end resection; however, a number of thereby promoting the initiation of DSB end resection,
recent studies have shed further light on this. The which is considered to help regulate the choice to repair
interaction between BRCA1 and CtIP within this DSBs via HR in S/G2 phase cells [36]. Moreover,
complex is mediated by CDK-dependent phosphoryla- BRCA1 has also been shown to reposition 53BP1 away
tion of CtIP-S327, whereas the ability of CtIP to pro- from DSB ends, thereby further facilitating end resec-
mote end resection is mediated CtIP-T847 tion (Fig. 1) [37–39]. Importantly, depletion of CtIP in
phosphorylation, which is also mediated by CDKs BRCA1/53BP1 null cells results in a loss of DSB end
during the S/G2 phases of the cell cycle [29,30]. By resection, indicating that CtIP is responsible for end
generating different knock-in cell lines containing ser- resection in the absence of BRCA1, although the role
ine to alanine phosphorylation abrogation mutations of BRCA1 within the BRCA1–C complex appears to
at these sites, these studies have demonstrated that comprises the repositioning of 53BP1 away from DSB
BRCA1 is dispensable for CtIP-mediated end resec- ends and/or the blocking of RIF1 recruitment to DSB
tion. Specifically, Reczek et al. [31] showed that ends [32]. Additionally, by initiating DNA end resec-
MEFs expressing CtIP S326A (equivalent to S327A in tion and the subsequent generation of RPA-coated
humans) displayed similar levels of Rad51 and RPA ssDNA, the BRCA1–C complex assists in the activa-
recruitment to DBSs as CtIP wild-type cells, indicat- tion of the ATR/Chk1 pathway responsible for intra-S
ing that the interaction between CtIP and BRCA1 is phase arrest, thereby preventing the replication of
not required for DNA end resection. Accordingly, a damaged DNA and promoting the maintenance of
loss of the CtIP-BRCA1 interaction did not affect genomic stability (Fig. 1).
HR or tumour development in mice [31]. Polato et al. Additional to the role of the BRCA1–C complex in
[32] reported similar findings, also showing that, in 53BP1 repositioning and initiation of resection, end

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BRCA1 and maintenance of genomic stability K. I. Savage and D. P. Harkin

Fig. 1. BRCA1 complexes involved in HR-

mediated DSB repair and cell cycle
checkpoint control. During the S and G2
phases of the cell cycle, DSBs are
faithfully repaired through HR. Initially,
53BP1 is displaced from DSB ends by the
BRCA1–C complex, which then initiates
DSB end resection. Both the BRCA1–C
and –B complexes, along with other
proteins such as Exo1 and DNA2, are
required to extend DNA end resection.
Both the BRCA1–C and –B complexes are
also required for activation of the Intra-S
checkpoint after DNA damage.
Additionally, the BRCA1–A complex is
recruited to flanking chromatin and is
thought to prevent over resection of DSB
ends. The BRCA1–A complex is also
required for maintained DNA damage
response signaling and activation of the
G2/M checkpoint. Finally, the BRCA1–D
complex facilitates the exchange of RPA
bound to the single-stranded DNA
overhangs with Rad51. Rad51 then
catalyses the invasion of the sister
chromatid and alignment with the
complementary DNA sequence within,
forming a Holiday junction. DNA
polymerases restore the complementary
DNA strand using the sister chromatid as
a template. The Holiday junction in then
resolved, resulting in noncross-over or
cross-over products, depending on the
direction of junction resolution.

resection is extended to facilitate RPA loading and surrounding DSBs, simultaneously required for contin-
subsequent RPA-Rad51 exchange prior to sister strand ued/extended resection. The exact steps in this process
invasion [34,36–39]. The repositioning of 53BP1 alone remain unclear, although it is known that reposition-
is not sufficient to facilitate resection with subsequent ing of RAP80 requires BRCA1 and POH1, a deubiqui-
repositioning of RAP80, also bound to the chromatin tinating enzyme and component of the proteasome,

634 FEBS Journal 282 (2015) 630–646 ª 2014 FEBS

K. I. Savage and D. P. Harkin BRCA1 and maintenance of genomic stability

which may function to locally degrade RAP80, facili- to these sites is less clear. Recruitment and binding of
tating the clearance of RAP80 and allowing end resec- DSB repair factors can be sub-compartmentalized into
tion. Intriguingly, another BRCA1 complex, the two different regions surrounding the DSB: (a) factors
BRCA1–A complex, which itself contains RAP80 that localize at DSB ends defined by regions of ssDNA
along with MERIT40, BRCC36/45 and Abraxas, has and (b) factors that localize to the chromatin flanking
been reported to inhibit DNA end resection, suggest- ssDNA regions [48].
ing that, in some contexts, BRCA1 may function to Intriguingly, BRCA1 has been identified in both
limit and/or prevent over resection of DNA breaks micro-compartments and the temporal recruitment of
[40,41]. This complex has also been shown to stabilize/ BRCA1 to DNA break sites has been shown to be
maintain DNA damage signaling from the break site biphasic, with a rapid c-H2AX independent stage of
and promote G2/M checkpoint arrest after DNA dam- recruitment followed by late c-H2AX-dependent
age (Fig. 1). recruitment. This suggests that BRCA1 may play dis-
Another BRCA1 complex, the BRCA1–B complex tinct roles at different times and regions at DSB ends
containing BRCA1/TopBP1 and BACH1 (also known and the flanking chromatin [48–50]. Shedding light on
and BRIP1/FANCJ) has been reported to play a role this, a recent study by Li and Yu [51] found that the
in HR and S-phase cell cycle arrest. The exact role of rapid c-H2AX independent recruitment of BRCA1 is
this complex in HR remains unclear, although it is mediated by binding of PARylated (poly(ADP-ribosy-
assumed that BACH1, a DNA helicase, contributes to lated)) substrates surrounding the DSB through the
end resection (possibly through its helicase activity) BRCT domains of BARD1, which is obligately bound
and RPA loading, whereas TopBP1 is required for to BRCA1. Given that this rapid recruitment
ATR activation and subsequent S-phase checkpoint of BRCA1 to DSB ends occurs independently of
activation (Fig. 1) [42]. c-H2AX and that recruitment of the BRCA1–A
Finally, after resection, another BRCA1 complex, complex is dependent on c-H2AX, it is tempting to
the BRCA1/BRCA2/PALB2/Rad51 complex (hereon hypothesize that recruitment of the BRCA1–A com-
referred to as the BRCA1–D complex), functions to plex may occur after recruitment of BRCA1 in other
promote the exchange of RPA for Rad51, and facili- DSB-binding complexes. This may explain how the
tate sister chromatid invasion. It is assuemd that the BRCA1–B and –C complexes initiate and contribute
BRCA1–D complex facilitates the recruitment of to DNA end resection, whereas the BRCA1–A com-
PALB2, BRCA2 and Rad51 to DSB sites and that plex, which is likely recruited after this step, inhibits
perhaps BRCA1 assists BRCA2 and Rad51 to pro- end resection. This hypothesis provides a model where
mote strand invasion (Fig. 1) [43,44]. BRCA1 within distinct macromolecular complexes,
Exactly, how the BRCA1–A, –B, –C and –D com- and recruited to the DSB ends and flanking chromatin
plexes are recruited to DSB sites remains unclear. at different times, is capable of initiating/promoting
Recruitment of the BRCA1–A complex to DSB sites DSB end resection, as well as preventing over resection
has been well characterized and this occurs through a in flanking chromatin and assisting in the exchange of
complex pathway involving recognition and binding of RPA/ssDNA for Rad51/ssDNA (Fig. 2). This model
phosphorylated H2AX (c-H2AX) at break sites by provides an overarching picture of how multiple differ-
MDC1 [45]. MDC1 itself is then phosphorylated, ent BRCA1 containing complexes are able to fine-tune
forming a binding site for RNF8, an E3 ubiquitin the HR process to faithfully repair DSBs and help to
ligase that ubiquitinates histones H2A, H2B and safeguard the genome.
H2AX surrounding the break site. These ubiquitinated BRCA1 has also been shown to form an S-phase
histones are then recognized/bound by a second E3 specific complex with Rad51 and FANCD2, a protein
ubiquitin ligase, RNF168, through its ubiquitin inter- mutated in a subgroup of Fanconi anaemia patients, a
action motif, allowing amplification of the ubiquitin genomic instability syndrome characterized by cellular
signal on histones flanking the DSB [46,47]. The sensitivity to DNA cross-linking agents [52]. This com-
BRCA1–A complex is then recruited to c-H2AX plex appears to function exclusively to repair replica-
marked chromatin surrounding the DSB through the tion forks stalled at DNA interstrand cross-links
recognition and binding of ubiquitinated histones by (ICLs). Within this repair process, BRCA1 is consid-
RAP80, which contains two ubiquitin interaction ered to localize mono-ubiquitinated FANCD2 to ICL
motifs. sites where it is required for ICL incision [53]. This
Despite the well-understood process by which the function of BRCA1 appears to be distinct from its
BRCA1–A complex is recruited to DSBs, the recruit- roles in HR because, although concomitant loss of
ment of the other HR promoting BRCA1 complexes BRCA1 and 53BP1 can restore HR and resistance to

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BRCA1 and maintenance of genomic stability K. I. Savage and D. P. Harkin

NER is also utilized to repair actively transcribed

DNA templates, known as transcription coupled
repair, a process in which both Msh2 and Msh6 are
involved [56]. In addition, BRCA1 has been shown to
be required for transcription coupled repair of oxida-
tive-8-oxoguanine lesions [57]. A mechanism for
BRCA1 in this pathway has been suggested involving
the BRCA1/BARD1 ubiquitin ligase-mediated degra-
dation of RNA Pol II, thereby allowing access for the
repair machinery [58,59]. Another mechanism through
which BRCA1 may contribute to NER is via the
transactivation of the xeroderma pigmentosum C and
DDB2 (damaged DNA binding) proteins, both of
Fig. 2. Model for recruitment of BRCA1 complexes to DNA DSBs.
Recruitment of BRCA1 to DSBs is biphasic. After DSB induction,
which are involved in NER (the involvement of
histones around DSBs are rapidly PARylated by PARP1. BRCA1 in transcriptional activation is discussed
Additionally, once activated, ATM phosphorylates histone H2AX, further below) [60].
forming c-H2AX. (1) Rapid recruitment of BRCA1–B and –C
complexes to DSB ends, where they initiate and extend end
resection, is mediated through the BARD1 BRCT domains, which BRCA1 forms multiple transcriptional
recognize PARylated histones at DSB ends. (2) By contrast, the complexes that contribute to genome
late recruitment of BRCA–A complexes to DSB flanking chromatin, stability
where it is hypothesized to prevent over resection of DNA ends,
occurs through the recognition of c-H2AX by MDC1 and the As well as promoting DNA repair and genome stabil-
subsequent activation of a ubiquitin signaling cascade, leading to ity directly, BRCA1 is known to form multiple com-
recruitment of the BRCA1–A complex through binding of the plexes that regulate the transcription of genes involved
BRCA1 BRCT domains to phosphorylated Abraxas. This model in many cellular processes, including DNA repair
suggests that BRCA1, within distinct macromolecular complexes (Fig. 3).
and recruited to the DSB ends and flanking chromatin at different
A role for BRCA1 in transcription was first sug-
times, is capable of initiating/promoting DSB end resection, as well
as preventing over resection in flanking chromatin. Whether the
gested by Miki et al. [1] in 1994 as a result of the high
BRCA1-D complex is recruited to DSBs in the rapid or late phase is number of acidic amino acid residues in its C-termi-
unknown, although it is likely to be recruited to DSB ends, where it nus. BRCA1 transactivation activity was then demon-
facilitates the exchange of RPA for Rad51. strated with experiments using the C-terminus of
BRCA1 fused to the GAL4 DNA binding domain
[14]. In addition, tumour derived mutations in the
poly ADP ribose polymerase (PARP) inhibitors (which C-terminus of BRCA1 abolished GAL4-BRCA1-
explicitly require HR-mediated repair), mice with a mediated transactivation and growth suppression, sug-
combined deletion of BRCA1 and 53BP1 remain sensi- gesting a physiological role for BRCA1 transcriptional
tive to DNA interstrand cross-linking agents, such as regulation [14,61].
cisplatin and mitomycin C [34,54]. This suggests the It is now widely accepted that BRCA1 affects tran-
BRCA1/RAD51/FANCD2 complex may function as scription in a number of ways. First, BRCA1 is known
an independent BRCA1 protein complex that protects to regulate signaling pathways that affect transcription
the genome against replication fork associated ICLs. factor activation. For example, BRCA1 phosphoryla-
In addition BRCA1 has been implicated in the tion in response to DNA damage by ATM and ATR
nucleotide excision repair (NER) pathway as a result at serines –1423 and –1524 is required for ATM-medi-
of its involvement in the BASC complex (BRCA1- ated p53 signaling and activation, thus regulating p53-
associated genome surveillance complex), which dependent p21 transcription [62]. In addition, BRCA1
includes MLH1, ATM, BLM, the MRN complex and appears to modulate which p53 target genes are trans-
the NER proteins Msh2 and Msh6 [55]. The NER activated in response to DNA damage, with BRCA1
pathway is utilized to repair DNA base modifications/ promoting the transcription of DNA repair and cell
adducts, such as those caused by UV irradiation and cycle arrest targets but not pro-apoptotic genes regu-
DNA alkylating agents. The process involves the exci- lated by p53 [63,64].
sion of a 24–32-bp fragment of DNA surrounding the By contrast to its role in promoting apoptosis,
adducted base followed by re-synthesis and ligation BRCA1 has also been shown to inhibit apoptosis
using the complementary strand as a template [56]. through the formation a complex with the p65 subunit

636 FEBS Journal 282 (2015) 630–646 ª 2014 FEBS

K. I. Savage and D. P. Harkin BRCA1 and maintenance of genomic stability

Fig. 3. BRCA1 transcriptional complexes.

BRCA1 forms multiple transcriptional
complexes with the ability to both co-
repress or co-activate genes involved in
different cellular processes. The proteins
with which BRCA1 binds to form
transcriptional activation complexes are
coloured yellow, whereas co-repressor
complex partners are coloured red. The
functions of genes regulated by these
different complexes are also highlighted.

of the activation of nuclear factor-kappa B (NF-jB) a subunit of the negative elongation factor complex,
transcriptional complex [65]. This complex constitu- also binds to ERa and inhibits ERa-mediated tran-
tively binds to the promoters of a number anti-apopto- scription by stalling RNA Pol II-mediated transcrip-
tic NF-jB target genes, including BCL2 and XIAP. In tional elongation [70].
response to DNA damage, BRCA1 recruits the p50 BRCA1 has also been associated directly with DNA
subunit of NF-jB to BRCA1/p60 bound promoters, promoters. BRCA1 does not contain any known DNA
resulting in transactivation of anti-apoptotic NF-jB binding domains and does not bind DNA in a
targets, including BCL2 and XIAP, thereby inhibiting sequence specific manner. Instead, BRCA1 forms dif-
apoptosis and inducing cellular resistance to DNA ferent transcription regulating complexes and is
damage [65]. recruited to promoters via interaction with sequence
The estrogen response signaling pathway is also specific transcription factors within these complexes.
known to be affected by BRCA1 at multiple different Consistent with this, we have shown that BRCA1 is
levels. Estrogens translocate into the nucleus where recruited to the ERa promoter by the octamer binding
they bind to the estrogen receptor-a (ERa), stimulating protein Oct-1, where it is required for ERa expression
receptor dimerization and activation. Activated ERs [71]. Interestingly, we showed that RNA Pol II is pres-
then bind estrogen response elements proximal to or ent on the ERa promoter irrespective of BRCA1 pro-
within promoters and stimulate the transcription of moter occupancy, suggesting, at least in the case of
target genes. Estrogen in general, promotes prolifera- ERa, that BRCA1 does not recruit the core transcrip-
tion and drives the expression of a number of prolifer- tional machinery. Thus, exactly how BRCA1 stimu-
ative genes associated with cancer and subsequent lates transcription from the ERa promoter is
genomic instability, such as cyclins E and D, the pro- unknown, although it is probably via recruitment of
gesterone receptor, epithelial growth factor and vascu- secondary factors and/or chromatin remodeling fac-
lar endothelial growth factor [66]. The link between tors. Indeed, BRCA1 is known to bind to a number of
estrogen signaling and the development of breast can- chromatin remodeling factors such as the histone de-
cer is indicated by the potent efficacy of treatment of acetylases HDAC1 and HDAC2, and the BRG1 and
this disease with anti-estrogen drugs such as tamoxi- BRD7 components of the SWI/SNF chromatin remod-
fen. BRCA1 is known to bind to ERa and is reported eling complex [72–74]. Although SWI/SNF-mediated
to repress both ligand-dependent and independent chromatin remodeling requires only the BRG1–
ERa signaling [67,68]. Concurrent with this, BRCA1 BAF155 minimal complex, transcriptional activation
severely represses the expression of a number of requires an activation domain [75]. Thus, it is assumed
endogenous ERa regulated genes, such as vascular that BRCA1 may provide this activation domain. In
endothelial growth factor, a protein implicated in addition to regulating ERa expression, BRCA1 and
tumour growth and angiogenesis [69]. In addition, Oct-1 are known to co-operate in the transactivation
wild-type BRCA1 inhibits proliferative signaling to the of the DNA damage-induced cell cycle inhibitor and
extracellular signal-related kinase by a membrane pro-apoptotic gene GADD45, thereby preventing the
bound isoform of ERa. Another BRCA1 binding pro- propagation of damaged DNA to daughter cells and/
tein known as COBRA1 (i.e. a co-factor of BRCA1), or promoting apoptosis, again contributing to the

FEBS Journal 282 (2015) 630–646 ª 2014 FEBS 637

BRCA1 and maintenance of genomic stability K. I. Savage and D. P. Harkin

maintenance of genomic stability [76,77]. Furthermore, ATR-dependent phosphorylation events after DNA
BRCA1/Oct-1 transcriptional activation complex has damage (as well as other phosphorylation and sumoy-
been shown to transactivate the expression of OGG1, lation events), it is conceivable that these phos-
NTH1 and REF1/APE1, which three key proteins phorylation events, or indeed DNA damage-induced
within the base excision repair pathway, with BRCA1- modification of BRCA1 binding proteins, may regulate
dependent expression of these genes being required for the activity and/or composition of proteins within
resistance to H2O2-mediated oxidative stress [78]. various BRCA1 promoter bound complexes, thereby
In addition to Oct-1 and p53-mediated BRCA1 allowing the fine tuning of BRCA1-regulated transcrip-
transactivation, BRCA1 functions as a transcriptional tion in response to different types of genotoxic stress.
co-activator with a number of other transcription fac-
tors, such as the signal transducer and activator of
A BRCA1-mRNA splicing complex that
transcription protein, Stat-1. BRCA1 co-activates a
promotes genomic stability
number of Stat-1 regulated genes such as the pro-
apoptotic genes IRF7, MxA 2,5 OAS and ISG54 in BRCA1 has been reported to form a large DNA
response to interferon-c stimulation damage-induced protein complex containing RNA
Although BRCA1 transactivates GADD45 in and hnRNP proteins, suggesting it may form a com-
response to DNA damage, it has also been reported to plex that regulates RNA processing after DNA dam-
repress GADD45 transcription in unperturbed cells, a age [86]. Accordingly, a new BRCA1 complex
mechanism that also requires the DNA damage involved in mRNA splicing has been identified. This
response protein, CtIP [79–81]. The BRCA1/CtIP/ complex includes BRCA1, BCLAF1, U2AF35/65,
Zbrk1 complex has subsequently been shown to Prp8 and SF3B1 and forms in response to DNA
repress over a dozen genes including the DNA repair damage. BRCA1 is recruited to this complex in a
genes RFC1 and HMGA2 [82]. Zbrk1-mediated tran- BCLAF1-dependent manner after the phosphorylation
scriptional repression requires the Kap1 co-repressor, of BRCA1 on serine-1423 in response to DNA dam-
which recruits the histone methyltransferase SETDB1 age [87]. Through this assembly mechanism, BRCA1
and the methylhistone binding protein HP1, resulting recruits the core mRNA splicing machinery to a large
in chromatin compaction and transcriptional repres- subgroup of BRCA1 bound promoters, and promotes
sion. Exactly how BRCA1 is involved in this repres- the efficient mRNA splicing of these genes. Upregu-
sion mechanism remains unknown; however, Zbrk1- lated splicing of these genes, many of which are
mediated GADD45 repression does not occur in the involved in DNA repair and maintenance of genomic
absence of BRCA1 [81]. BRCA1 also acts as a tran- stability, appears to maintain the expression of pro-
scriptional co-repressor in a complex with c-Myc and teins that are turned over more rapidly after DNA
the c-Myc interacting protein Nmi (n-myc-interacting damage, such as ATRIP, BACH1 and EXO1 (all of
protein), where it represses a number of cancer associ- which are proteins involved in HR-mediated DSB
ated genes,such as hTERT and psoriasin (S100A7) repair). As a result, depletion of core components of
[83,84]. this complex, such as BCLAF1 or U2AF65, results in
The finding that BRCA1 forms part of, and is defective DNA DSB repair and subsequent genomic
required for, both the Gadd45 pre-damage transcrip- instability.
tional repression complex (BRCA1/Zbrk1) and the It should be noted that, when carrying out these
post-damage transcriptional activation complex studies, we found that BCLAF1 depletion was unable
(BRCA1/Oct1) suggested that BRCA1 may receive to further sensitize BRCA1 mutant cells to IR using
and/or transduce some sort of ‘switch’ signal to pro- clonogenic survival assays, suggesting that BRCA1
moter binding proteins and/or the repression/activation and BCLAF1 function in an epistatic manner within
machinery in response to DNA damage. Indeed, work the same pathway. However, clonogenic survival
from our own labotarory, which set out to define the assays only demonstrate long-term cellular survival
BRCA1 transcriptome, found that BRCA1 is bound to after a specific genotoxic insult and do not allow the
a large subset of promoters throughout the genome, functional separation of different pathways that con-
although it does not regulate the transcription of the tribute to cell death. Therefore, although demonstrat-
majority of these genes in unperturbed cells [85]. How- ing that the pathway in which BRCA1 and BCLAF1
ever, in response to various stresses, such as DNA cooperate is required for cellular survival after IR, it is
damage, the expression of many of these genes is unlikely that all of the tumor-suppressive function of
regulated in a BRCA1-dependent manner. Given BRCA1 is mediated through its role in mRNA splicing
that BRCA1 is highly modified by ATM- and with BCLAF1 alone.

638 FEBS Journal 282 (2015) 630–646 ª 2014 FEBS

K. I. Savage and D. P. Harkin BRCA1 and maintenance of genomic stability

Intriguingly, BRCA1 has been previously reported group has demonstrated that estrogen and its metabo-
to inhibit 30 mRNA poly-adenylation, and thereby lites are capable of causing S-phase specific DNA
mRNA stability, through BRCA1/BARD1 ubiquitin- DSBs, which appear to be induced through the col-
dependent degradation of RNA-Pol II [58]. This sug- lapse of stalled replication forks during DNA replica-
gests a general role for the BRCA1/BARD1 complex tion [94]. The same study also found that BRCA1 was
in blocking active transcription on a genome wide level required for the repair of estrogen and estrogen metab-
after DNA damage, presumably to prevent the tran- olite-mediated DSBs and that depletion of BRCA1, or
scription of damaged genes. Despite this, it is accepted indeed heterozygous mutation of BRCA1, as is the
that specific genes, for example ATRIP, are actively case in BRCA1 mutation carriers, lead to defective
transcribed in response to DNA damage, suggesting repair of estrogen metabolite-induced DSBs and subse-
an additional mechanism that facilitates the transcrip- quent genomic instability. Importantly, estrogen-
tion/expression of a subset of genes in the context of a induced DNA damage and genomic instability occurs
more genome wide shutdown of transcription. We pro- independently of ERa. Intriguingly, the study also
pose that, as part of this mechanism, BRCA1 recruits found that BRCA1 directly transcriptionally represses
the mRNA splicing machinery to a subset of promot- the expression of the estrogen metabolizing enzyme
ers of genes required for an efficient DNA damage CYP1A1, resulting in reduced estrogen metabolism
response (such as ATRIP, BACH1 and EXO1), thereby and estrogen-mediated DNA damage in human breast
promoting the co-transcriptional splicing of these cells.
genes, positively regulating the stability of their tran- It is well accepted that estrogen levels in human
scripts and subsequent protein expression. breast cells are up to six- to seven-fold higher than
that of other tissues. Therefore, it is likely that the
increased estrogenic burden on these tissues requires
BRCA1 tissue-specific tumourigenesis
the co-ordinated effort of multiple BRCA1 functional
It is clear that BRCA1 plays a role in multiple differ- complexes, including DNA repair and transcriptional
ent protein complexes, many of which contribute complexes functioning together, to protect breast and
either directly or indirectly to the maintenance of ovarian cells from estrogen-induced genomic instability
genomic stability. However, given that BRCA1 plays and subsequent tumourigenesis.
this role in many, if not all, cells within the body, one In addition, studies have demonstrated that a
of the most perplexing features of BRCA1 mutation is BRCA1 transcriptional complex, involving the NRF2
that it predominantly predisposes carriers to cancers of transcription factor, drives antioxidant gene expres-
the breast and ovaries: both representing estrogen-reg- sion, resulting in a reduction in toxic reactive oxygen
ulated tissues. Several observations suggest estrogen species [95]. Subsequently, it was shown that loss of
has an important role in the development of BRCA1- the BRCA1/NRF2-mediated antioxidant response,
dependent breast cancer. Oophorectomy in BRCA1 upon BRCA1 depletion, generally leads to apoptosis.
mutation carriers significantly reduces the risk of However, in breast cells, estrogen is able to promote
breast cancer onset and recurrence [88–90]. Further- the NRF2-dependent antioxidant response in a
more, pregnancy increases the risk of early-onset BRCA1 independent manner, through a PI3K/mTOR-
breast cancer in BRCA1 mutation carriers, in contrast dependent pathway [96]. Finally, estrogen was shown
to noncarriers for whom pregnancy is protective [91]. to stimulate the survival of BRCA1 deficient breast
Estrogen is postulated to promote tumourigenesis cells, which would normally undergo apoptosis, and it
directly through stimulation of ERa and the down- was suggested that this may allow cells exposed to
stream activation of pro-mitogenic transcriptional pro- higher levels of estrogen, such as those in the breast
grams. However, this is confounded by observations and ovaries, to accumulate further tumourigenic muta-
that approximately 70–80% of BRCA1 mutated breast tions, such as the TP53 or PTEN mutations usually
tumours are ERa negative [92,93]. Furthermore, found in BRCA1 mutated breast and ovarian tumours.
BRCA1 drives ERa expression, suggesting the role of
estrogen in BRCA1-dependent tumour development
Therapeutic implications of BRCA1
may be independent of ERa [71].
function
However, an ERa independent mechanism for estro-
gen-mediated tumourigenesis has been postulated,
Cancer therapy
through the endogenous conversion of estrogen to
genotoxic metabolites, which could then trigger geno- Given that BRCA1 plays such a determinate role in
mic instability. Indeed, recent work from our own the DNA damage response, including the promotion

FEBS Journal 282 (2015) 630–646 ª 2014 FEBS 639

BRCA1 and maintenance of genomic stability K. I. Savage and D. P. Harkin

of DNA DSB repair and cell cycle checkpoint arrest, it loss of other components of the HR repair pathway.
should not be unexpected that BRCA1 plays an impor- Based on these issues, we recently developed and inde-
tant role in modulating the response to genotoxic pendently validated a gene expression signature,
chemotherapeutic agents. A number of preclinical termed DDRD, that identifies breast tumours with an
studies have shown that BRCA1 drives resistance to a underlying DNA repair defect [101]. More impor-
number of commonly used DNA damaging chemo- tantly, we see the same biology in multiple different
therapeutics, such as etoposide, bleomycin and the cancers, suggesting that the assay can be translated
platinum compounds cisplatin and carboplatin [97]. across different tumour types for the purpose of
Consistent with this, a number of retrospective clinical patient selection.
studies have shown that patients whose tumours
express low levels of BRCA1 respond better to plati-
Chemoprevention in BRCA1 carriers
num-based therapy compared to those whose tumours
express moderate or high levels of BRCA1 [97,98]. By Currently, women in the UK who carry a BRCA1
contrast, BRCA1 appears to mediate sensitivity to an- mutation are offered more intensive screening and risk
timicrotubule agents; however, the mechanism behind reducing mastectomy and/or oophorectomy. The only
this remains unknown [97] . other risk-reduction strategy available to these women
More recently, the DNA double-strand break repair is chemoprevention. The selective ER modulators
defect in BRCA1 mutated cells has been exploited to (SERMs) tamoxifen and raloxifene are recommended
identify a synthetically lethal relationship with loss or for use in high-risk women in the UK. However, evi-
inhibition or PARP1 [99]. An initial report by Farmer dence for the benefit of tamoxifen as a chemopreven-
et al. [99] demonstrated that BRCA1 and 2 deficient tive agent in BRCA1 mutation carriers is conflicting.
cells were exquisitely sensitive to inhibition of PARP1 One small study [102] showed no benefit from tamoxi-
using small molecule inhibitors of this protein. PARP1 fen in reducing breast cancer risk in BRCA1 mutation
is a core component of the base excision repair path- carriers, although it has been suggested that tamoxifen
way, within which it functions to signal SSBs through use in BRCA1 mutation carriers with breast cancer
the poly-ADP-ribosylation of histones around the may reduce the incidence of contralateral tumours
SSB. It is assumed that inhibition of PARP1 leads to [103,104]. Additionally, given that the majority of
an accumulation of SSBs which, when met by the tumours that develop in BRCA1 mutation carriers are
advancing replication fork during DNA synthesis, ER negative, it is unlikely that SERMs will reduce
results in replication fork stalling. Rescue of stalled breast cancer risk. Moreover, our own findings demon-
replication forks requires a functional HR pathway strating that estrogen can promote genomic instability
involving BRCA1. Therefore, in BRCA1/HR deficient (i.e. an early hallmark of BRCA1 mutant tumours)
cells, PARP1 inhibition leads to replication fork col- independently of the estrogen receptor cast some
lapse, resulting in an accumulation of unrepaired mechanistic doubt on the efficacy of SERMS as
DSBs and cell death. A number of different PARP chemopreventive agents in BRCA1 carriers.
inhibitors are currently being investigated in both A phase III trial termed the Prevention of Breast
breast and ovarian cancer clinical trials where BRCA1 Cancer by Letrozole in Postmenopausal Women carry-
is known to be mutated. In addition, further clinical ing a BRCA1/2 Mutation (LIBER) ([Link]
trials are being conducted in other cancer types such number NCT00673335) is currently enrolling postmen-
as prostate and pancreatic cancers with an underlying opausal women for treatment with letrozole, an aro-
defect in HR-mediated DNA repair pathways [100]. matase inhibitor (AI) that leads to reduced estrogen
One of the outstanding issues in the appropriate use of synthesis and circulating estrogen levels in postmeno-
PARP inhibitors across multiple cancer types relates pausal women, aiming to evaluate its ability to prevent
to the need for appropriate biomarker to select the development of breast cancer in patients with a
patients that are likely to respond to this type of tar- BRCA1/2 mutation.
geted therapy. The direct sequencing of BRCA1 is one However, AIs may have little preventative effect in
method already being used to select patients for enrol- premenopausal women, in whom the majority of
ment in PARP inhibitor trials. However, this approach BRCA1-linked tumours develop, and in whom estro-
is not without its issues because not all BRCA1 muta- gen production occurs predominantly in the ovaries
tions will result in a repair defect. Furthermore, this through an aromatase independent biosynthesis path-
approach will not identify those patients who are likely way. In these women, oophorectomy has been shown
to respond to PARP inhibitors through epigenetic to reduce the risk of breast cancer by up to 60% [105].
inactivation of BRCA1 or indeed through mutation or Taking our findings into account, it may also be worth

640 FEBS Journal 282 (2015) 630–646 ª 2014 FEBS

K. I. Savage and D. P. Harkin BRCA1 and maintenance of genomic stability

considering the use of AIs as an additional chemopre- obscured by the reported role of 53BP1 in transcrip-
ventive strategy in premenopausal women, many of tion, such as in the co-activation of p53 target genes (a
whom have undergone risk-reducing oophorectomy role also played by BRCA1), which could also account
without mastectomy. for the rescue of tumour suppression in BRCA1/
Finally, in premenopausal women who have opted 53BP1 null mice [109]. Nevertheless, the contribution
not to undergo risk-reducing oophorectomy or mastec- of the roles of 53BP1 and BRCA1 in transcriptional
tomy, luteinizing hormone-releasing hormone agonists regulation and with respect to tumour suppression is
may prove useful as chemopreventive agents. These still difficult to quantify and more research will be
drugs cause reversible ovarian suppression/ablation needed to tease out the exact mechanistic impact of
and are currently used in combination with tamoxifen the functions of BRCA1. Nonetheless, it is clear
or AIs for the treatment of premenopausal women that the specific knowledge of BRCA1 biology gained
with ERa positive breast cancer [106,107]. over the last 20 years has had a significant impact on
the development of new therapeutic strategies, which
should result in a meaningful impact on cancer treat-
Conclusions
ment.
Subsequent to the initial discovery of BRCA1, consid-
erable progress has been made in understanding the
Author contribution
cellular functions of this protein. This has lead to the
discovery of new genes/proteins involved in cancer pre- Both authors conceived the ideas and wrote the manu-
disposition and progression, the use of surgical inter- script.
vention to reduce the risk of cancer in mutation
carriers, and the development of targeted therapies for
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