BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Word Cloud By Danielle Smolyar
Interest in BRCA1 stems from its role as a tumour suppressor in breast and ovarian cancer. Intensive research in BRCA1 has revealed little about its specific role in cancer; rather, this protein has been implicated in a multitude of important cellular processes.
The diverse biochemical activities of BRCA1 combine to protect the genome from damage.
New data reveal that BRCA1
- transcriptionally regulates some DNA-repair genes, and, in addition,
- new roles for BRCA1 have been identified in heterochromatin formation on the X chromosome,
- doublestrand break repair, and
- ubiquitination.
BRCA1 functions in several processes, but it is unclear how these relate to the BRCA1 requirement in all cell types. Similar to the p53 tumour suppressor, BRCA1 activates genes encoding the DNA-repair response. Unlike p53, BRCA1 also has a direct role in the repair process.
According to the earlier suggested model, BRCA1–BARD1 functions in genome surveillance by scanning active genes in association with the holo-pol, and when the elongating transcription complex encounters DNA lesions, BRCA1 initiates a repair response. It is interesting to note that a BRCA1-binding cofactor, COBRA1, which regulates BRCA1 function in a chromatin decompression assay, has been found to be a required subunit of a complex that regulates transcription elongation.
When damage is encountered on the DNA template, the lesion could be corrected by transcription-coupled repair (step 1), a known BRCA1 function. Alternatively, some types of damage might require that the polymerase be removed to effect repair. Since the polymerase synthesizing mRNA on a DNA template is quite stably bound, it has been hypothesized that BRCA1 would then ubiquitinate the polymerase signaling its degradation (step 2).
Although current evidence does not implicate BRCA1 in this process, the polymerase is ubiquitinated and degraded following DNA damage. The residual BRCA1 complex might remain bound to the DNA lesion.
BRCA1 has been found to bind DNA cruciforms and three-way junctions, such as might occur at damage sites (step 3). This bound BRCA1 would then recruit repair factors, such as the RAD50-containing complex, which would then mend the lesion (steps 4 and 5).
One might infer from the recruitment of the H2AX kinase to sites in which BRCA1 is bound to DNA that this surveillance of the template by transcription results in BRCA1-dependent degradation of the transcription apparatus and recruitment of the H2AX kinase to nucleate the assembly of a repair focus.
Although there is no yeast homolog for BRCA1, perhaps a analogous pathway is conserved in this organism, mediated by a transcription elongation factor that is genetically linked in this pathway to holo-pol components.
The key cellular functions assigned to BRCA1 are numerous. BRCA1 can interact with many cellular proteins and pathways, but how these many interactions address the key questions of required ubiquitous function and tumour suppressing breast and ovarian cell function are unclear. These diverse activities of BRCA1 may be linked in a single pathway, or BRCA1 might function in multiple nuclear processes.
Source References:
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Dr. Saha, good post. There is a very interesting therapeutic strategy now concerning the BRCA1/2 mutant patient. It has been shown that PARP inhibitors are extremely effective in BRCA1/2 patients as there can still be NHEJ repair (nonhomogous recombination repair) which the PARP inhibitor will take care of. This was discovered because PARP inhibitors are not that effective in BRCA1/2 wild type patients. This might be a great post. Look up University of Pennsylvania which is doing a tril on this in breast/ovarian. Also a friend of mine at Kansas, Dr. Thuy Vy Do in the lab of Dr. Andy Godwin is doing similar research. I certainly could talk to them for you and set up a connection if you’d like.
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.