[GRG] Role Of Folded DNA Revealed

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The human genome is sprinkled throughout with mysterious folded DNA structures known as i-motifs. At last week’s American Chemical Society meeting in Dallas, scientists reported a long-awaited role for these structures, along with closely related hairpinlike ones: i-Motifs activate gene expression, and the hairpins repress it.

The scientists developed small molecules targeting each of these structures and used them to unravel the molecular mechanism of the gene activation and repression process. The findings suggest such molecules could be used to make cancer cells more vulnerable to existing therapeutics

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The researchers concluded that i-motifs and related hairpins are a promising new class of drug targets—not only for treating cancer but potentially for other therapeutic indications as well.

The work was carried out by pharmaceutical sciences professor Laurence H. Hurley and nuclear magnetic resonance spectroscopist Danzhou Yang of the University of Arizona, professor of chemistry and biochemistry Sidney M. Hecht of Arizona State University, bioanalytical chemistHanbin Mao of Kent State University, and coworkers. Hurley and Mao reported on the work in a Division of Medicinal Chemistry symposium. The team also describes it in three recent papers (J. Am. Chem. Soc. 2014, DOI:10.1021/ja410934b and 10.1021/ja4109352; Nucl. Acids Res. 2014, DOI: 10.1093/nar/gku185).

“It’s the sort of evidence we’ve been waiting for,†said i-motif expert John A. Brazier of England’s University of Reading, in that the role of i-motifs had been suspected but not confirmed. “I’m really quite gutted because we were hoping to publish on the first small molecule to stabilize an i-motif, but they beat us to it.â€

i-Motifs are kissing cousins to G-quadruplexes, folded genomic DNA structures that are already known to control gene expression, which has made them targets of ongoing drug discovery efforts. G-quadruplexes are cubelike conformations that form in single strands of genomic DNA. In the same genomic locations, complementary single strands can form i-motifs, which resemble bent, cross-linked paper clips. The i-motifs exist in equilibrium with more-flexible hairpins.

The team identified a piperidine derivative (called IMC-48) and a pregnanol derivative (IMC-76) that modulate gene expression by interacting with i-motifs or corresponding hairpins. Binding and stabilizing i-motifs or hairpins switches gene expression on or off, respectively.

The mechanism by which these structures control gene expression became apparent when the researchers used the small molecules in cancer cells with overactive BCL2, a gene that is overexpressed in cancer. They found that an endogenous transcription factor called hnRNP LL recognizes and binds to an i-motif in BCL2, activating gene transcription. But it doesn’t recognize the flexible hairpin structure. Using IMC-76 to stabilize the hairpin thus turns off gene expression, making the cancer cells more susceptible to the chemotherapy drug etoposide, the study shows.

The approach has been patented and licensed for further development to TetraGene, in Salt Lake City, a start-up Hurley cofounded.

“Can we see this equilibrium in other i-motif-forming sequences†and thus potentially extend the approach to other medical conditions, besides cancer? Brazier asked. “That would be the next step.â€

Chemical & Engineering News

ISSN 0009-2347

Copyright © 2014 American Chemical Society

Best,

Elizabeth Parrish

liz,l.parrish Skype

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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