Molecule identified that contributes to essential cell functioning process
New research from the University of North Carolina at Chapel Hill has identified a cellular enzyme that helps regulate the synthesis of proteins essential to cell functioning throughout the life of the organism. The enzyme binds to histone messenger RNA, which is DNAs blueprint for histone protein synthesis.
As histones represent about half of the nucleoprotein complex known as chromatin, they are vital to DNA replication and the subsequent assembly of chromosomes A report of the research appears in the Aug. 29 edition of the science journal Molecular Cell.
“This is the first enzyme Im aware of thats specific for a particular group of messenger RNAs,” said Dr. William F. Marzluff, professor of biochemistry and biophysics at UNCs School of Medicine.
“We think this novel enzyme halts the synthesis of histones when theyre no longer needed by rapidly degrading histone mRNAs. This is important because too much histone synthesis can be lethal to the cell.”
Marzluffs focus on histone mRNA stems largely from his teams 1996 discovery and cloning of the stem-loop binding protein SLBP. A major regulatory player in histone mRNA expression, SLBP latches onto the looped tail of histone mRNA and signals the synthesis of histone proteins. In addition, SLBP remains bound to histone mRNA, making sure that its instructions are properly translated.
But SLBPs role in the rapid destruction of histone mRNA when histone synthesis is no longer needed has remained unclear. “Now we have another protein – this enzyme called 3-prime histone mRNA exonuclease – that binds to the same region and also binds to SLBP,” said study lead author Dr. Zbigniew Dominski, associate professor of biochemistry and biophysics at UNC. “And they bind together in a very short region, where we had thought there was only one protein at any one time.”
The protein had been identified previously but had not been characterized, Dominski said – that is, its function was unknown. “No one had studied it. They just knew it existed.”
RNA affinity purification, genome database comparison and mass spectrometry at the medical schools proteomics facility helped identify the protein as a 3-prime exonuclease. “When we saw that one of its domains was this 3-prime exonuclease, we immediately realized it must be linked to histone mRNA degradation,” Dominski said.
Cloning the exonuclease allowed further study, which indicated that the protein initiated degradation of histone mRNA. “When this protein and SLBP are bound to the stem-loop at the same time, the exonuclease is inactive. When SLBP drops off, rapid histone mRNA degradation occurs. Therefore, SLBP helps to coordinate both the synthesis and the degradation of histone mRNA,” Marzluff said. Dominski added, “The intriguing thing about this is having two proteins bound to this very small target at the same time. Its a unique molecular mechanism. Wed like to figure out how that happens chemically and exactly how this interaction occurs.”
Along with Marzluff and Dominski, UNC co-authors include Xiao-cui Yang and Handan Kaygun. Co-author Dr. Michael Dadlez is from Warsaw University in Poland. Support for the research came from the National Institutes of Health.
In February 2001, UNC Chancellor James Moeser announced a campuswide genomics initiative representing a public-private investment of at least $245 million over the next 10 years.
By Leslie H. Lang
UNC School of Medicine
Note: Contact Marzluff at 919-962-2140 or 962-8920 or firstname.lastname@example.org. Contact Dominski at 919-962-2141 or email@example.com. School of Medicine contact: Les Lang, 919-843-9687 or firstname.lastname@example.org.
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