Hexbyte Glen Cove Study identifies never-before-seen dual function in enzyme critical for cancer growth thumbnail

Hexbyte Glen Cove Study identifies never-before-seen dual function in enzyme critical for cancer growth

Hexbyte Glen Cove

This cartoon demonstrates the three-dimensional structure of the pol theta enzyme. Credit: S. Doublie, University of Vermont

Considered the most lethal form of DNA damage, double-strand breaks must be repaired to prevent cell death. In developing therapies for hard-to-treat breast and ovarian cancers in patients with BRCA gene mutations, scientists aim to identify ways to keep cancer cells from using DNA break repair pathways. New findings demonstrate a previously-unknown capability for polymerase theta (pol theta) – a key enzyme in this repair function—that shows promise as a new avenue for treatment development.

The study results are published in Molecular Cell.

Researchers at the University of Vermont (UVM), The University of Texas MD Anderson Cancer Center (MD Anderson), and Yale University discovered that pol theta, previously known to extend DNA in the repair process, is also able to behave like a nuclease and trim DNA.

Because these rely on the pol theta pathway to survive and repair double-strand breaks, researchers have been focused on pol theta and trying to find out how to inhibit this pathway.

“Pol theta is a ‘hot’ enzyme right now,” says senior author and self-described “polymerase geek” Sylvie Doublié, Ph.D., professor of microbiology and molecular genetics at the UVM Larner College of Medicine and the UVM Cancer Center. “This is a new activity for pol theta; it’s an elegant way of solving the problem—you only need one enzyme.”

For patients with hard-to-treat cancers, this finding could lead to the development of new therapeutic options, like the Poly-ADP-ribose polymerase (PARP) inhibitors class of drugs that have been used to treat breast and ovarian over the past decade.

“The cell has to decide which function needs to be applied and this trimming activity is a point of vulnerability for pol theta,” says Doublié. One aim of the research is to create conditions where one reaction can be encouraged over the other.

A potential role for such an inhibitor would be to improve ionizing radiation therapy in cancer patients with BRCA1 or BRCA2 mutations.

Doublié’s former doctoral student Karl Zahn, Ph.D., now a postdoctoral fellow at Yale, saw evidence of this dual function in pol theta several years ago while working in Doublié’s lab. He carried out the experiments described in the paper after engaging the expertise of Richard Wood, Ph.D., professor of epigenetics and molecular carcinogenesis at MD Anderson. Wood and Doublié have had a long-term collaboration, funded by a Program Project grant from the National Cancer Institute.

Conducting the experiments, controls, and reproducing the findings took the research team several years but was critical to confirming this discovery.

“It was an unexpected finding, and the biochemistry makes sense, suggesting a way to inhibit the DNA repair process orchestrated by pol theta”, says Wood.

“The trimming reaction is rapid, and many people missed it,” says Doublié, adding that the research team’s patience and work paid off. “‘Chance favors only the prepared mind,'” she says, quoting the late French scientist Louis Pasteur.

Study identifies never-before-seen dual function in enzyme critical for cancer growth (2021, February 11)
retrieved 11 February 2021
from https://phys.org/news/2021-02-never-before-seen-dual-function-enzyme-critical.html

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Relapse Prevention

Relapse Prevention

The 3 Stages of Relapse
A relapse typically doesn’t occur as a spur-of-the-moment event. In most cases, there are three main stages of relapsing. Understanding these stages, and what to do when they occur, can help stop a relapse before it takes effect.

The 3 stages of relapse include:

1. Emotional Relapse
During an emotional relapse, a person is not consciously thinking about drinking. However, their emotions and behaviors are setting the stage for a relapse.

During this stage, denial plays a big role. Many of the signs that occur during emotional relapse are also symptoms of post-acute withdrawal (PAWS). To help minimize the risk of relapse, it is important to recognize that many of the uncomfortable feelings you experience in early addiction recovery could be symptoms of PAWS.

Symptoms of PAWS include:

Foggy thinking/trouble remembering
Urges and cravings
Irritability or hostility
Sleep disturbances, such as insomnia or vivid dreams
Issues with fine motor coordination
Stress sensitivity
Anxiety or panic
Lack of initiative
Impaired ability to focus
Mood swings
Emotional relapse warning signs include:

Anger and irritability
Mood swings
Bottling up emotions
Isolation and not asking for help
Not attending support groups (or attending and not sharing)
Poor self-care (not eating, sleeping, or practicing good personal hygiene)

Hexbyte Glen Cove The chemistry lab inside cells thumbnail

Hexbyte Glen Cove The chemistry lab inside cells

Hexbyte Glen Cove

(A) X-ray crystal structure of QhpG and schematic of crosslinked QhpC. The substrate QhpC is bound to the pocket formed by the catalytic domain, which includes the FAD cofactor and the small domain. (B) QhpG-catalyzed dihydroxylation reaction. Credit: Osaka University

Investigators from the Institute of Scientific and Industrial Research at Osaka University, together with Hiroshima Institute of Technology, have announced the discovery of a new protein that allows an organism to conduct an initial and essential step in converting amino acid residues on a crosslinked polypeptide into an enzyme cofactor. This research may lead to a better understanding of the biochemistry underlying catalysis in cells.

Every living cell is constantly pulsing with an array of biochemical reactions. The rates of these reactions are controlled by special proteins called enzymes, which catalyze specific processes that would otherwise take much longer. A number of enzymes require specialized molecules called “cofactors,” which can help shuttle electrons back and forth during oxidation-reduction reactions. But these cofactors themselves must be produced by the organisms, and often require the assistance of previously existing proteins.

Now, a team of scientists at Osaka University has identified a novel protein called QhpG that is essential for the biogenesis of the cofactor cysteine tryptophylquinone (CTQ). By analyzing the mass of the reaction products and determining its , they were able to deduce the catalytic function of QhpG, which is adding two to a specific tryptophan residue within an active-site subunit QhpC of quinoheme protein amine dehydrogenase, the bacterial enzyme catalyzing the oxidation of various primary amines. The resulting dihydroxylated tryptophan and an adjacent cysteine residue are finally converted to cofactor CTQ.

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Hexbyte Glen Cove Novel analytical tools developed by SMART key to next-generation agriculture thumbnail

Hexbyte Glen Cove Novel analytical tools developed by SMART key to next-generation agriculture

Hexbyte Glen Cove

Species-independent analytical platforms can facilitate the creation of feedback-controlled high-density agriculture. Credit: Betsy Skrip, Massachusetts Institute of Technology

Researchers from the Disruptive & Sustainable Technologies for Agricultural Precision (DiSTAP) Interdisciplinary Research Group (IRG) of Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore, and Temasek Life Sciences Laboratory (TLL), highlight the potential of rapid and non-destructive analytical tools that provide tissue-cell or organelle-specific information on living plants in real time and can be used on any plant species.

In a perspective paper titled “Species-independent analytical tools for next-generation agriculture,” published in the scientific journal Nature Plants, SMART DiSTAP researchers report that they used two engineered plant nanosensors and portable Raman spectroscopy to detect biotic and , monitor plant hormonal signaling and characterize soil, phytobiome and crop health in a non-invasive or minimally invasive manner. The researchers discuss how the tools bridge the gap between model in the laboratory and field application for agriculturally relevant plants. They also provide an assessment of the future outlook, economic potential and implementation strategies for the integration of these technologies in future farming practices.

According to U.N. estimates, the global population is expected to grow by 2 billion within the next 30 years, giving rise to an expected increase in demand for food and agricultural products to feed the growing population. Today, biotic and abiotic environmental stresses such as , sudden fluctuations in temperature, drought, soil salinity, and toxic metal pollution—made worse by climate change—impair crop productivity and lead to significant losses in agriculture yield worldwide.

An estimated 11 to 30% yield loss of five major crops of global importance (wheat, rice maize, potato, and soybean) are caused by crop pathogens and insects; with the highest crop losses observed in regions already suffering from food insecurity. Against this backdrop, research into innovative technologies and tools are required for sustainable agricultural practices and meet the rising demand for food and food security—an issue that has drawn the attention of governments worldwide due to the COVID-19 pandemic.

The Plant nanosensors were developed at SMART DiSTAP. They are smaller than the width of a hair and can be inserted into the tissues and cells of plants to understand complex signaling pathways. The portable Raman spectroscopy, also developed at SMART DiSTAP, is a portable laser-based device that measures molecular vibrations induced by laser excitation, producing highly specific Raman spectral signatures that provide a fingerprint of a plant’s health. These tools are able to monitor stress signals in short time scales, ranging from seconds to minutes, allowing for early detection of stress signals in real-time.

“The use of plant nanosensors and Raman spectroscopy has the potential to advance our understanding of crop health, behavior, and dynamics in agricultural settings,” said Dr. Tedrick Thomas Salim Lew, the paper’s first author and a recent graduate student of the Massachusetts Institute of Technology (MIT). “Plants are highly complex machines within a dynamic ecosystem, and a fundamental study of its internal workings and diverse microbial communities of its ecosystem is important to uncover meaningful information that will be helpful to farmers and enable sustainable farming practices. These next-generation tools can help answer a key challenge in plant biology, which is to bridge the knowledge gap between our understanding of model laboratory-grown plants and agriculturally-relevant crops cultivated in fields or production facilities.”

Early plant stress detection is key to timely intervention and increasing the effectiveness of management decisions for specific types of stress conditions in plants. The development of these tools capable of studying plant health and reporting stress events in real-time will benefit both plant biologists and farmers. The data obtained from these tools can be translated into useful information for farmers to make management decisions in real-time to prevent yield loss and reduced crop quality.

The species-independent tools also offer new study opportunities in plant science for researchers. In contrast to conventional genetic engineering techniques that are only applicable to model plants in laboratory settings, the new tools apply to any which enables the study of agriculturally-relevant crops previously understudied. The adoption of these tools can enhance researchers’ basic understanding of plant science and potentially bridge the gap between model and non-model plants.

“The SMART DiSTAP interdisciplinary team facilitated the work for this paper and we have both experts in engineering new agriculture technologies and potential end-users of these technologies involved in the evaluation process,” said Professor Michael Strano, the paper’s co-corresponding author, DiSTAP co-lead Principal Investigator, and Carbon P. Dubbs Professor of Chemical Engineering at MIT. “It has been the dream of an urban farmer to continually, at all times, engineer optimal growth conditions for plants with precise inputs and tightly controlled variables. These tools open the possibility of real-time feedback control schemes that will accelerate and improve plant growth, yield, nutrition, and culinary properties by providing optimal growth conditions for plants in the future of urban farming.”

“To facilitate widespread adoption of these technologies in agriculture, we have to validate their economic potential and reliability, ensuring that they remain cost-efficient and more effective than existing approaches,” the paper’s co-corresponding author, DiSTAP co-lead Principal Investigator, and Deputy Chairman of TLL Professor Chua Nam Hai explained. “Plant nanosensors and Raman spectroscopy would allow farmers to adjust fertilizer and water usage, based on internal responses within the plant, to optimize growth, driving cost efficiencies in resource utilization. Optimal harvesting conditions may also translate into higher revenue from increased product quality that customers are willing to pay a premium for.”

Collaboration among engineers, plant biologists, and data scientists, and further testing of new tools under field conditions with critical evaluations of their technical robustness and economic potential will be important in ensuring sustainable implementation of technologies in tomorrow’s agriculture.

DiSTAP Scientific Advisory Board Members, Professor Kazuki Saito, Group Director of Metabolomics Research Group at RIKEN Center for Sustainable Resource Science, and Hebrew University of Jerusalem Professor, Oded Shoseyov also co-authored the paper.

More information:
Tedrick Thomas Salim Lew et al. Species-independent analytical tools for next-generation agriculture, Nature Plants (2020). DOI: 10.1038/s41477-020-00808-7. www.nature.com/articles/s41477-020-00808-7