10:19pm Monday 25 September 2017

Important Human Genetic Structures Identified for the First Time

STRATFORD, N.J. – Genetic information transferred within cells plays an essential role both in the healthy function of the human body and in changes within cells that can trigger serious disease. New research led by Dmitry Temiakov, Ph.D., of UMDNJ-School of Osteopathic Medicine, has identified important mechanisms of this genetic transfer process for the first time. These new findings, published in the journal Nature, open the door to developing potential therapies for several serious diseases including cancers. They also add to basic knowledge of the functioning of the healthy human body.

Each human cell harbors small organelles called mitochondria, which are responsible for the energy production of the cell, and therefore are often called the cell’s “power plant.” Mitochondria contain their own genome which is maternally inherited and encodes numerous genes of proteins that are involved in energy production. Mitochondria are also believed to fuel harmful processes that can lead to the development of conditions that include diabetes, cancer and Parkinson’s disease, as well as the onset of cognitive impairment and other conditions associated with aging. Because of this, therapy that targets the actions of mitochondria may be a promising strategy for mitigating and even reversing these illnesses, making understanding of molecular mechanisms of mitochondrial gene expression an important goal for researchers.

The current research sought to uncover structural information about mitochondrial (human) RNA polymerase, the key enzyme in the process of transferring genetic information from mitochondrial DNA to RNA, the molecule that carries that information to structures within cells that govern those cells’ function in the body. Mitochondrial RNA polymerase does not directly share its sequence or structural homology (common evolutionary origin) with large multi-subunit cellular RNA polymerases, the variety that appears in organisms such as bacteria and also in the nuclei of human cells.

The lack of commonality between two distinct varieties of polymerase that co-exist within human cells has intrigued the scientific community. Thus, the structure of multi-subunit RNA polymerase II has been a subject of intensive studies, including by Nobel Laureate Roger Kornberg. In 1984 David Clayton and colleagues demonstrated that mitochondrial RNA polymerase is related to a polymerase found in a small virus of E.coli bacterium, called phage T7. This was a surprising finding since it is believed that mitochondria originated from an endosymbiotic relationship (where one organism hosts the other) formed between bacteria and eukaryotes (cells that are the building blocks of organisms that include humans) and thus that the majority of mitochondrial proteins have bacterial homologies. Until now, specific structures and pathways involved could not be identified.

The team led by Temiakov sought to make such an identification by teaming up with the lab of one of the world’s leading crystallographers, Prof. Patrick Cramer in Gene Center, Munich, Germany (http://www.lmb.uni-muenchen.de/cramer/patrickCramer/index.htm). The project was initiated about four years ago but only last year the team was able to obtain large, well-diffracting crystals of an active form of human mitochondrial polymerase. The structure was solved in Cramer’s lab and reveals the mechanistic adaptations that occurred during evolution of a self-sufficient T7-like RNA polymerase to become regulated by transcription initiation factors. It is the first-ever representation of mitochondrial polymerase.

Temiakov says he and his colleagues were thrilled to make their discovery. “I would compare our own excitement about this structure with what anthropologists experience when they find an ancient hominid and can see changes in the skull and other bones that occurred during an evolution and resulted in modern human beings.”

The structural information can be used to understand how mitochondrial polymerase binds DNA, interacts with other mitochondrial proteins and regulates expression of mitochondrial genes under different conditions. This knowledge will guide many future biochemical and genetic experiments and will help to validate mitochondrial polymerase as a therapeutic target.

Journalists who wish to interview Dmitry Temiakov, Ph.D., are invited to contact Rob Forman, UMDNJ Chief of News Services, at 973-972-7276 or formanra@umdnj.edu .

The University of Medicine and Dentistry of New Jersey (UMDNJ) is the nation’s largest free-standing public health sciences university with more than 6,000 students on five campuses attending the state’s three medical schools, its only dental school, a graduate school of biomedical sciences, a school of health related professions, a school of nursing and New Jersey’s only school of public health. UMDNJ operates University Hospital, a Level I Trauma Center in Newark, and University Behavioral HealthCare, which provides a continuum of healthcare services with multiple locations throughout the state.

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