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Archive - Mar 5, 2011

Novel Mechanism for Control of Gene Expression

Researchers at Boston University have discovered a novel, evolutionarily conserved mechanism for the regulation of gene expression. The new work by Dr. David Levin and Dr. Ki-Young Kim is reported in the March 4, 2011 issue of Cell. Normal cell growth, embryonic development, and responses to stress, require proper spatial and temporal control of gene expression. Studies on control of transcription (RNA biosynthesis) are typically centered on understanding how the RNA polymerase is recruited to the promoter, the control region of a gene. However, the new work has revealed the existence of a second level of control in a yeast model system. The researchers found that genes expressed solely under certain stress conditions are normally maintained in a silent state by a process called transcriptional attenuation. In attenuation, the RNA polymerase initiates transcription of the gene, but its progress is terminated prematurely by a termination complex that binds to the polymerase. Attenuation occurs commonly in bacteria, but was not previously known to operate in eukaryotic cells (those with a nucleus). “In response to an inducing stress signal, attenuation must be overcome so that a target gene can be expressed,” said Dr. Levin. “The way that works in this instance is that an activating transcription factor, called Mpk1, serves double duty—it is first responsible for recruitment of the RNA polymerase to the promoter, but Mpk1 then binds to the transcribing polymerase to block association of the termination complex.” Mutations in a human protein, called Senataxin, which is related to a component of the yeast termination complex, are responsible for causing juvenile-onset forms of ALS and ataxia, two neuromuscular degenerative diseases. In their new research, Dr. Levin and Dr.

New Details on Key Protein in Lou Gehrig’s Disease

Amyotrophic lateral sclerosis, known as ALS or more popularly, Lou Gehrig's disease, is a notorious neurodegenerative condition characterized by the progressive deterioration of brain and spinal cord neurons, resulting in the gradual but catastrophic loss of muscle control and ultimately, death. In a new paper, published in the Feb. 27 advance online edition of the journal Nature Neuroscience, a team of scientists at the University of California, San Diego School of Medicine and colleagues describe the profound and pervasive role of a key RNA-binding protein called TDP-43 in ALS pathology. It has previously been shown that, when mutated, TDP-43 can cause ALS. The new work on TDP-43 was led by Dr. Don W. Cleveland, professor and chair of the UCSD Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research and Dr. Gene Yeo, assistant professor in the Department of Cellular and Molecular Medicine. In normal cells, TDP-43 is found in the nucleus where it helps maintain proper levels of RNA. In the majority of ALS patients, however, TDP-43 accumulates in the cell's cytoplasm and thus is excluded from the nucleus, which prevents it from performing its normal duties. Using a mouse model, the researchers made three new important findings: First, employing a comprehensive genome-wide RNA-binding mapping strategy, they discovered that more than one-third of the genes in the mouse brain are direct targets of TDP-43. In other words, the roles and functions of these genes are impacted by the presence – or absence – of normal TDP-43. Second, the genes most affected had numerous TDP-43 binding sites on very long introns. Introns are the non-coding portions of a gene that are not used to make proteins.