CSHL scientists discover new way in which ubiquitin modifies transcriptional machinery to regulate gene activityDecember 19, 2008During gene transcription - the process inside the nucleus of cells by which DNA, the genetic material, is copied into RNA - a large, ever-changing multiprotein complex is enlisted to assist the DNA-copying enzyme in its challenging job. Like an exquisitely choreographed dance, each step in the process has to be performed with precision, in order for the copy to be accurate and useful in subsequent events. These events culminate in a version of the RNA copy exiting the nucleus and serving as the template for the production of new proteins. Scientists have documented a host of mechanisms involved in the assembly and behavior of the "helper" protein complex. A team at Cold Spring Harbor Laboratory (CSHL) has now discovered a mechanism, which, according to Professor William P. Tansey, Ph.D., "provides a paradigm for how the components [of the helper complex] could be disassembled and how the complex falls apart." Their results will appear in the December 16th issue of Proceedings of the National Academy of Sciences. A "wedge" in transcription One of the mechanisms that influences critical interactions in transcription is called ubiquitylation. It involves the addition of small protein molecules called ubiquitin to other, larger proteins. When ubiquitin "tags" are added to these larger molecules, it has the effect of marking them for destruction. Tansey's team has previously characterized how the ubiquitin-triggered destruction of transcription factors - proteins that help switch on genes - was connected to the regulation of gene activity. The addition of ubiquitin, however, was later found, in other contexts, to modify proteins in non-destructive ways, too. This suggested to Tansey the existence of a more benign link between transcription and ubiquitylation. Working with yeast cells, Tansey's team has now identified this link: a protein called Asr1. Understanding its role has enabled Tansey and colleagues to more comprehensively grasp how ubiquitin functions. They have discovered that Asr1 "glues" ubiquitin on to specific spots in the DNA-copying enzyme, called RNA polymerase II (abbreviated by scientists as RNA pol II). This enzyme is composed of 12 modules, each with a distinct function. When Asr1 binds to the enzyme, bits of ubiquitin that glom onto it form little wedge-like features between the enzyme's different modules. This causes two of the 12 modules to be jettisoned from the enzyme, thereby "inactivating" it. "The activity of Asr1 is an example of how ubiquitin can regulate gene transcription by using its non-destructive functions to pull a complex apart," says Tansey. A new class of proteins Along with other proteins that resemble it in structure, Asr1 is present in most multicellular organisms, and appears to be well conserved in most species, from yeast to humans. The fact that evolution has "preserved" them is an indication that this class of proteins performs an important job. The CSHL team made another notable discovery. They found that Asr1 has the unique ability of homing in on RNA pol II molecules that are actively turning on genes, while at the same time ignoring otherwise similar enzymes that remain idle. This fact, according to Tansey, suggests that Asr1 is a "negative" regulator of gene transcription. He hypothesizes that Asr1 might selectively glom on to RNA pol II molecules that are making mistakes in copying or copying DNA in the wrong location. It is also possible, according to Tansey, that Asr1's ubiquitin-adding ability enables it to help terminate the normal transcription process. In addition to pursuing experimental evidence of these possibilities, Tansey's team is now also hunting for other Asr1-like ubiquitin-adding proteins that may influence gene activity. "Modulation of RNA polymerase II subunit composition by ubiquitylation" will appear in the December 16th issue of Proceedings of the National Academy of Sciences. The full citation is: Anne Daulny, Fuqiang Geng, Masafumi Muratani, Jonathan M. Geisinger, Simone E. Salghetti, and William P. Tansey. The paper is available online at: http://www.pnas.org/content/105/50/19649.full Cold Spring Harbor Laboratory (CSHL) is a private, not-for-profit research and education institution at the forefront of efforts in molecular biology and genetics to generate knowledge that will yield better diagnostics and treatments for cancer, neurological diseases and other major causes of human suffering. Cold Spring Harbor Laboratory (CSHL) |
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| Related Gene Transcription Current Events and Gene Transcription News Articles How RNA polymerase II gets the go-ahead for gene transcription All cells perform certain basic functions. Each must selectively transcribe parts of the DNA that makes up its genome into RNAs that specify the structure of proteins. Cancer drug may improve memory in Alzheimer's patients A drug now used to treat cancer may also be able to restore memory deficits in patients with Alzheimer's disease. Protein plays unexpected role protecting chromosome tips A protein specialist that opens the genomic door for DNA repair and gene expression also turns out to be a multi-tasking workhorse that protects the tips of chromosomes and dabbles in a protein-destruction complex, a team lead by researchers at The University of Texas M. D. Anderson Cancer Center reports in the Aug. 13 edition of Molecular Cell. GUMC discovery highlights new direction for drug discovery In a discovery that rebuffs conventional scientific thinking, researchers at Georgetown University Medical Center (GUMC) have discovered a novel way to block the activity of the fusion protein responsible for Ewing's sarcoma, a rare cancer found in children and young adults. Cocaine-linked genes enhance behavioral effects of addiction New research sheds light on how cocaine regulates gene expression in a crucial reward region of the brain to elicit long-lasting changes in behavior. Getting down to cancer basics Researchers have identified a new cancer gene - one that is common to many cancers and affects the most basic regulation of our genes. The new example - a gene on the X chromosome called UTX - is found in 10% of cases of multiple myeloma and 8% of esophageal cancers. Scripps research team identifies key molecules that inhibit viral production The research, led by Professor Donny Strosberg of Scripps Florida, was published on March 4, 2009, in the Journal of General Virology's advance, online edition, Papers in Press. In the new study, Strosberg and his colleagues describe peptides (molecules of two or more amino acids) derived from the core protein of hepatitis C. The team found that these peptides inhibit not only dimerization of the core protein (the joining of two identical subunits), but also production of the actual virus itself. Scientists find gene that modifies severity of cystic fibrosis lung disease Researchers at Wake Forest University Baptist Medical Center, and colleagues, have identified a gene that modifies the severity of lung disease in people with cystic fibrosis, a lethal genetic condition. The findings open the door to possible new targets for treatment, researchers say. Rare disease provides clues about enzyme role in arrhythmias A University of Iowa study provides insight into a calcium-sensing enzyme already known to play a role in irregular heartbeats and other critical functions. Could vitamin D save us from radiation? Radiological health expert Daniel Hayes, Ph.D., of the New York City Department of Health and Mental Hygiene suggests that a form of vitamin D could be one of our body's main protections against damage from low levels of radiation. More Gene Transcription Current Events and Gene Transcription News Articles |
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