Reported by: Dr. V.S. Karra, Ph.D
Transcription is a cellular process by which genetic information from DNA is copied to messenger RNA for protein production. But anticancer drugs and environmental chemicals can sometimes interrupt this flow of genetic information by causing modifications in DNA.
Chemists at the University of California, Riverside have now developed a test in the lab to examine how such DNA modifications lead to aberrant transcription and ultimately a disruption in protein synthesis.
The chemists report that the method, called “competitive transcription and adduct bypass” or CTAB, can help explain how DNA damage arising from anticancer drugs and environmental chemicals leads to cancer development.
“Aberrant transcription induced by DNA modifications has been proposed as one of the principal inducers of cancer and many other human diseases,” said Yinsheng Wang, a professor of chemistry, whose lab led the research. “CTAB can help us quantitatively determine how a DNA modification diminishes the rate and fidelity of transcription in cells. These are useful to know because they affect how accurately protein is synthesized. In other words, CTAB allows us to assess how DNA damage ultimately impedes protein synthesis, how it induces mutant proteins.”
Study results appeared online in Nature Chemical Biology on Aug. 19.
Wang explained that the CTAB method can be used also to examine various proteins involved in the repair of DNA. One of his research group’s goals is to understand how DNA damage is repaired—knowledge that could result in the development of new and more effective drugs for cancer treatment.
“This, however, will take more years of research,” Wang cautioned.
His lab has a long-standing interest in understanding the biological and human health consequences of DNA damage. The current research was supported by the National Cancer Institute, the National Institute of Environmental Health Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
Wang was joined in the research by UC Riverside’s Changjun You (a postdoctoral scholar and the research paper’s first author), Xiaoxia Dai, Bifeng Yuan, Jin Wang and Jianshuang Wang; Philip J. Brooks of the National Institute on Alcohol Abuse and Alcoholism, Md.; and Laura J. Niedernhofer of the University of Pittsburgh School of Medicine, Penn.
Next, the researchers plan to use CTAB to investigate how other types of DNA modifications compromise transcription and how they are repaired in human cells.
A quantitative assay for assessing the effects of DNA lesions on transcription
Source:
University of California, Riverside
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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.