A team of researchers led by Dmitry Temiakov, PhD, of the Rowan University School of Osteopathic Medicine (RowanSOM), has discovered a molecular 'switch' that controls replication and transcription of mitochondria DNA, a key finding that could influence the development of targeted therapies for cancer, developmental processes related to fertility and aging. The research appears in the January 30 edition of Science.
"In a cell's nucleus, there are many complicated mechanisms that prevent replication and transcription from colliding," said Temiakov, an associate professor in RowanSOM's Department of Cell Biology. "In mitochondria, we found those are mutually exclusive processes, but we believe that we have identified the key player that effectively switches on or off transcription or replication."
Mitochondria are organelles located outside the nucleus of nearly every cell in humans. While most of the cell's DNA is inside the nucleus, mitochondria maintain their own DNA and contribute a small number of genes that are essential for cellular respiration and energy generation.
According to Karen Agaronyan, who is the study's lead author, the molecular switch is a mitochondrial transcription elongation factor called TEFM and it prevents the detrimental consequences -- including mutations -- of transcription/replication collisions. The RowanSOM study is the first to describe TEFM's role in controlling transcription and replication and highlights TEFM as a potential target for new drug therapies.
"We were studying transcription in the presence of this elongation factor (TEFM) when we discovered it also has an unexpected anti-termination activity," said Agaronyan, who is a doctoral student at RowanSOM.
What they found solved a mystery that had puzzled researchers for years. Scientists had observed that mitochondrial RNA polymerase (mtRNAP) would stop partway through the process of transcribing DNA. The RowanSOM researchers discovered that when TEFM is present, mtRNAP can go through the termination site to continue making full-size RNA transcripts.
"Changes in mitochondrial DNA copy number are associated with cancer and genetic diseases, as well as developmental processes like spermatogenesis, oogenesis and embryogenesis," Temiakov said. "Our study suggests that if we can understand how this switch works, we can affect the copy number. That, in turn, highlights TEFM as a possible target for drugs that can fight these diseases and enhance developmental processes."
This study was supported in part by a five-year $1.5 million grant from the National Institutes of Health (R01GM104231) awarded to Temiakov in 2013.
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