Breast cancer is a common malignancy, affecting 1 in 8 women. A major contributary factor in disease development lies in a positive family history, a correlation that is striking for early-onset breast cancer. Mutations in the DNA-damage repair protein BRCA1 [, ]are believed to be responsible for 45% of inherited breast cancer and more than 80% of inherited breast and ovarian cancer.The BRCA1 protein is a E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage [, ]. It contains an N-terminal zinc-finger domain. It also contains a BRCT C-terminal domain, an approximately 100 amino acid tandem repeat, which appears to act as a phospho-protein binding domain [].
This family consists of several cofactor of BRCA1 (COBRA1) proteins (also known as negative elongation factor B). It is thought that COBRA1 along with BRCA1 is involved in chromatin unfolding. COBRA1 is recruited to the chromosome site by the first BRCT repeat of BRCA1, and is itself sufficient to induce chromatin unfolding. BRCA1 mutations that enhance chromatin unfolding also increase its affinity for, and recruitment of, COBRA1. It is thought that that reorganisation of higher levels of chromatin structure is an important regulated step in BRCA1-mediated nuclear functions [].
Selective autophagy is mediated by autophagic cargo receptors such as p62, which facilitates docking of ubiquitinated substrates to the autophagosome []. NBR1 acts as a receptor that cooperates with p62 in the autophagic clearance of ubiquitinated substrates [, ]. NBR1 contains a C-terminal UBA domain that can bind mono- and polyubiquitin [].
This entry represents a group of plant BRCA1 C terminus (BRCT) domain-containing proteins, including At4g02110 from Arabidopsis. Their function is not clear.
The RING domain of the breast and ovarian cancer tumour-suppressor BRCA1 interacts with multiple cognate proteins, including the RING protein BARD1. Proper function of the BRCA1 RING domain is critical, as evidenced by the many cancer-predisposing mutations found within this domain. A dimer is formed between the RING domains of BRCA1 and BARD1. The BRCA1-BARD1 structure provides a model for its ubiquitin ligase activity, illustrates how the BRCA1 RING domain can be involved in associations with multiple protein partners and provides a framework for understanding cancer-causing mutations at the molecular level [].
BRAT1 binds to ATM and BRCA1 and is involved in DNA damage-induced ATM activation []. It is also involved in cell proliferation and mitochondrial functions []. Mutations of the BRAT1 gene have been linked to epileptic encephalopathy [, ].
Retinoblastoma-binding protein 8 (RBBP8), also known as CtIP, is an endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in processing meiotic and mitotic double-strand breaks (DSBs) by ensuring both resection and intrachromosomal association of the broken ends [, ]. CtIP interacts with the BRCA1 tumour suppressor []. BRCA1 and CtIP are required to recruit Dna2 at DSBs in homologous recombination, ensuring robust DSB resection []. CtIP it is not a tumuor suppressor itself, instead, it can promote tumourigenesis. This is probably related to its role in the formation of chromosomal rearrangements through the microhomology-mediated end joining (MMEJ) pathway, a relatively error-prone pathway of DSB repair [].
Ubiquitin-specific peptidase 51 (USP51, MEROPS identifier C19.065) is a de-ubiquitinating enzyme that has been shown to release ubiquitin from protein conjugates. It specifically deubiquitinates Lys-14 (H2AK13Ub) and Lys-16 (H2AK15Ub) of histone H2A, thus regulating the DNA damage response at double-strand breaks (DSBs). It is also involved in the assembly/disassembly of of TP53BP1 and BRCA1 [].
This entry represents the DNA ligase IV (Lig4) sequences between the two BRCA1 C-terminal (BRCT) domains. Lig4 along with Xrcc4 functions in DNA non-homologous end joining. This process is required to mend double-strand breaks. Upon ligase binding to an Xrcc4 dimer, the helical tails unwind leading to a flat interaction surface [].
CtIP is predominantly a nuclear protein that complexes with both BRCA1 and the BRCA1-associated RING domain protein (BARD1). At the protein level, CtIP expression varies with cell cycle progression in a pattern identical to that of BRCA1. Thus, the steady-state levels of CtIP polypeptides, which remain low in resting cells and G1 cycling cells, increase dramatically as Dividing cells traverse the G1/S boundary. CtIP can potentially modulate the functions ascribed to BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control []. This N-terminal domain carries a coiled-coil region and is essential for homodimerisation of the protein []. The C-terminal domain is family CtIP_C and carries functionally important CxxC and RHR motifs, absence of which lead cells to grow slowly and show hypersensitivity to genotoxins [].
This entry includes animal BRCA1 (BREAST CANCER SUSCEPTIBILITY 1) proteins and their homologues from plants [].The aimal BRCA1 protein is a E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage [, ]. It contains an N-terminal zinc-finger domain. It also contains a BRCT C-terminal domain, an approximately 100 amino acid tandem repeat, which appears to act as a phospho-protein binding domain []. Arabidopsis BRCA1-related proteins includes AtBRCA1(AT4G21070, ) and AtBARD1 (AT1G04020, ). Both are involved in DNA repair in plants [, ]. AtBRCA1 can be induced by gamma-rays []. AtBARD1, also known as Row1, functions mainly as a REPRESSOR OF WUSCHEL1, which is a transcription repressor required to regulate the maintenance of stem cell populations in shoot meristems [, ].
UBXN1 is a widely expressed protein containing an N-terminal ubiquitin-associated (UBA) domain, a coiled-coil region, and a C-terminal ubiquitin-like (UBX) domain. It binds polyubiquitin and valosin-containing protein (VCP), and has been identified as a substrate for stress-activated protein kinases (SAPKs) []. UBXN1 specifically binds to Homer2b []. It may also interact with ubiquitin (Ub) and may be involved in the Ub-proteasome proteolytic pathways. UBXN1 can associate with autoubiquitinated BRCA1 tumour suppressor and inhibit its enzymatic function through its UBA domain [].
Claspin is an essential protein for the ATR-Chk1-dependent activation ofthe DNA replication checkpoint response in Xenopus and human cells [, ]. DNA damage induces the formation of a complex between Claspin and BRCA1, a second regulator of Chk1 activation. It is thought that ATR regulates Claspin phosphorylation in response to DNA damage and replication stress, resulting in recruitment and phosphorylation of BRCA1. BRCA1 and Claspin then function to activate Chk1 [].This entry represents both claspin and claspin homologues found mainly in Drosophila.
Microcephalin is implicated in chromosome condensation and DNA damage induced cellular responses [, ]. It may play a role in neurogenesis and regulation of the size of the cerebral cortex in animals. It is a protein, which if expressed homozygously, causes the organism to have the condition microcephaly - a drastically reduced brain mass and volume []. Microcephalin is predicted to contain three BRCA1 C-terminal domains, the first of which is the probable microcephaly mutation site.
Microcephalin is implicated in chromosome condensation and DNA damage induced cellular responses [, ]. It may play a role in neurogenesis and regulation of the size of the cerebral cortex in animals. It is a protein, which if expressed homozygously, causes the organism to have the condition microcephaly - a drastically reduced brain mass and volume []. Microcephalin is predicted to contain three BRCA1 C-terminal domains, the first of which is the probable microcephaly mutation site. This entry includes non-mammalian uncharacterised proteins (from lower vertebrates and fungi) related to microcephalin.
PALB2 (partner and Localizer of BRCA2) binds to the N-terminal region of BRCA2, and is vital for its function by facilitating its subnuclear localization []. It binds BRCA1 and BRCA2 and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex, which is required for homologous recombination repair []. It has also been shown to bind DNA and physically interacts with RAD51 []. Biallelic mutations in PALB2 cause Fanconi anemia (FA) subtype FA-N, whereas monoallelic mutations predispose to breast, and pancreatic familial cancers[].
Members of protein family FAM175 include the BRCA1-A complex subunit Abraxas 1 [, ], BRISC complex subunit Abraxas 2 or Abro1 (Abraxas brother protein 1) [, ], and uncharacterised plant proteins.It is thought that BRCA1-A complex subunit Abraxas acts as a central scaffold protein responsible for assembling the various components of the BRCA1-A complex, and mediates recruitment of BRCA1 [, ]. Similarly, Abro1 probably acts as a scaffold facilitating assembly of the various components of BRISC []- the protein does not interact with BRCA1, but binds polyubiquitin []. The primary sequences of these proteins contain an MPN-like domain [].This entry represents the plant members of FAM175.
Members of protein family FAM175 include the BRCA1-A complex subunit Abraxas 1 [, ], BRISC complex subunit Abraxas 2 or Abro1 (Abraxas brother protein 1) [, ], and uncharacterised plant proteins.It is thought that BRCA1-A complex subunit Abraxas acts as a central scaffold protein responsible for assembling the various components of the BRCA1-A complex, and mediates recruitment of BRCA1 [, ]. Similarly, Abro1 probably acts as a scaffold facilitating assembly of the various components of BRISC []- the protein does not interact with BRCA1, but binds polyubiquitin []. The primary sequences of these proteins contain an MPN-like domain [].
Members of protein family FAM175 include the BRCA1-A complex subunit Abraxas 1 [, ], BRISC complex subunit Abraxas 2 or Abro1 (Abraxas brother protein 1) [, ], and uncharacterised plant proteins.It is thought that BRCA1-A complex subunit Abraxas acts as a central scaffold protein responsible for assembling the various components of the BRCA1-A complex, and mediates recruitment of BRCA1 [, ]. Similarly, Abro1 probably acts as a scaffold facilitating assembly of the various components of BRISC []- the protein does not interact with BRCA1, but binds polyubiquitin []. The primary sequences of these proteins contain an MPN-like domain [].This entry represents the Abro1 protein.
Members of protein family FAM175 include the BRCA1-A complex subunit Abraxas 1 [, ], BRISC complex subunit Abraxas 2 or Abro1 (Abraxas brother protein 1) [, ], and uncharacterised plant proteins.It is thought that BRCA1-A complex subunit Abraxas acts as a central scaffold protein responsible for assembling the various components of the BRCA1-A complex, and mediates recruitment of BRCA1 [, ]. Similarly, Abro1 probably acts as a scaffold facilitating assembly of the various components of BRISC []- the protein does not interact with BRCA1, but binds polyubiquitin []. The primary sequences of these proteins contain an MPN-like domain [].This entry represents the Abraxas 1 protein.
The breast cancer susceptibility gene contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control [, , ]. The BRCT domain is not limited to the C-terminal of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT. BRCT domains are often found as tandem-repeat pairs []. Some data []indicate that the BRCT domain functions as a protein-protein interaction module.The structure of the first of the two C-terminal BRCT domains of the human DNA repair protein XRCC1 has been determined by X-ray crystallography [].Structures of the BRCA1 BRCT domains revealed a basis for a widely utilised head-to-tail BRCT-BRCT oligomerization mode []. This conserved tandem BRCT architecture facilitates formation of the canonical BRCT phospho-peptide interaction cleft at a groove between the BRCT domains. BRCT domains disrupt peptide binding by directly occluding this peptide binding groove, or by disrupting key conserved BRCT core folding determinants [].
The breast cancer susceptibility gene contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control [, , ]. The BRCT domain is not limited to the C-terminal of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT. Some data []indicate that the BRCT domain functions as a protein-protein interaction module.The structure of the first of the two C-terminal BRCT domains of the human DNA repair protein XRCC1 has been determined by X-ray crystallography, it comprises a four-stranded parallel β-sheet surrounded by three α-helices, which form an autonomously folded domain [].
This entry represents E3 ubiquitin-protein ligase RNF8, which may be required for proper exit from mitosis after spindle checkpoint activation and may regulate cytokinesis. This enzyme promotes the formation of 'Lys-63'-linked polyubiquitin chains and functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer [, ]. Substrates that are poly-ubiquitinated at 'Lys-63' are usually not targeted for degradation. RNF8 acts following DNA double-strand break (DSB) formation, and is recruited to the sites of damage by ATM-phosphorylated MDC1, where it promotes the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF) [, ]. It may play a role in the regulation of RXRA-mediated transcriptional activity, but is not involved in RXRA ubiquitination by UBE2E2.Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1, ), a ubiquitin-conjugating enzyme (E2, ), and a ubiquitin ligase (E3, , ), which work sequentially in a cascade. There are many different E3 ligases, which are responsible for the type of ubiquitin chain formed, the specificity of the target protein, and the regulation of the ubiquitinylation process []. Ubiquitinylation is an important regulatory tool that controls the concentration of key signalling proteins, such as those involved in cell cycle control, as well as removing misfolded, damaged or mutant proteins that could be harmful to the cell. Several ubiquitin-like molecules have been discovered, such as Ufm1 (), SUMO1 (), NEDD8, Rad23 (), Elongin B and Parkin (), the latter being involved in Parkinson's disease [].
This entry represents XPG (ERCC-5, alsoknown as Rad2 in budding yeast, AtRAD2 or UVH3 in Arabidopsis and Rad13 in fission yeast), a single-stranded structure-specific DNA endonuclease, which cleaves single-stranded DNA during nucleotide excision repair to excise damaged DNA []. It makes the 3' incision in DNA nucleotide excision repair (NER); it binds and bends DNA repair bubble substrate and breaks base stacking at the single-strand/double-strand DNA junction of the DNA bubble [, ]. XPG is required for DNA replication fork maintenance and preservation of genomic stability [, ]. It is involved in homologous recombination repair (HRR) induced by DNA replication stress by recruiting RAD51, BRCA2, and PALB2 to the damaged DNA site []. During HRR, binds to the replication fork with high specificity and stabilizes it []and upstream of HRR, it promotes the release of BRCA1 from DNA [].In Saccharomyces cerevisiae, Rad2 forms the Nucleotide Excision Repair Factor 3 (NEF3) complex with a subset of subunits of the transcription factor TFIIH []. Besides DNA damage repair, it is also required for efficient transcription []. Defects in XPG are the cause of xeroderma pigmentosum complementation group G (XP-G), which is an autosomal recessive pigmentary skin disorder characterised by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities [].
This presumed domain can be found in CCRA1/CCRA2 from animals and RSA1 from plants. Cell division cycle and apoptosis regulator protein 1 (CCRA1, also known as CARP-1) is a transcriptional coactivator for nuclear receptors which may contribute to cell growth and apoptosis [, ]. It can act as a both a coactivator and corepressor of the transcription dependent on the androgen receptor (AR), thereby playing an important role in the growth and tumorigenesis of prostate cancer cells []. Cell cycle and apoptosis regulator protein 2 (CCRA2, also known as DBC-1) is a core component of the DBIRD complex, which regulates alternative splicing []. It is also involved in p53-mediated apoptosis [], genomic stability and cellular integrity following UV-induced genotoxic stress [], tumour suppression []and BRCA1 activity []. In Arabidopsis thaliana, SHORT ROOT IN SALT MEDIUM 1 (RSA1, also known as EMB1579) is required for salt tolerance and sodium (Na) homeostasis after salt stress []. RSA1 is localised to the nucleus and the loss of function of RSA1 affects global transcription and mRNA splicing [].
This presumed domain can be found in CCRA1/CCRA2 from animals and RSA1 from plants. Cell division cycle and apoptosis regulator protein 1 (CCRA1, also known as CARP-1) is a transcriptional coactivator for nuclear receptors which may contribute to cell growth and apoptosis [, ]. It can act as a both a coactivator and corepressor of the transcription dependent on the androgen receptor (AR), thereby playing an important role in the growth and tumorigenesis of prostate cancer cells []. Cell cycle and apoptosis regulator protein 2 (CCRA2, also known as DBC-1) is a core component of the DBIRD complex, which regulates alternative splicing []. It is also involved in p53-mediated apoptosis [], genomic stability and cellular integrity following UV-induced genotoxic stress [], tumour suppression []and BRCA1 activity []. In Arabidopsis thaliana, SHORT ROOT IN SALT MEDIUM 1 (RSA1, also known as EMB1579) is required for salt tolerance and sodium (Na) homeostasis after salt stress []. RSA1 is localised to the nucleus and the loss of function of RSA1 affects global transcription and mRNA splicing [].
The breast cancer type 2 susceptibility protein (BRCA2) is a breast tumour suppressor involved in double-strand break repair and/or homologous recombination []. BRCA2 gene expression is regulated in a cell-cycle dependent manner and peak expression of BRCA2 mRNA occurring in S phase, suggesting BRCA2 may participate in regulating cell proliferation. BRCA2, and related protein BRCA1, have transcriptional activation potential and the two proteins are associated with the activation of double-strand break repair and/or homologous recombination. The two proteins have been shown to coexist and colocalize in a biochemical complex. BRCA2 has a number of 39 amino acid repeats []that are critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment [, , ]. There are eight repeats in BRCA2 designated as BRC1 to BRC8. BRC1, BRC2, BRC3, BRC4, BRC7, and BRC8 have high sequence identity and bind to Rad51, whereas BRC5 and BRC6 are less well conserved and are unable to bind Rad51 []. It has been suggested that BRCA2 plays a role in positioning Rad51 at the site of DNA repair or in removing Rad51 from DNA once repair has been completed.Mutations in BRCA1 and BRCA2 have been linked to an elevated risk of young onset breast cancer and confer a high risk of the disease through a dominantly inherited fashion []. BRCA2 mutations are typically microdeletions.Homologues exist in plants: the BRCA2A and BRCA2B proteins from Arabidopsis thalianaare required for repair of breaks in double-stranded DNA and homologous recombination and in the prophase stage of meiosis are required for formation of RAD51 and DMC1 foci in males [].
