FLASH dances with death and mRNA

Whether it was Daniel DeFoe or Benjamin Franklin, whoever coined the phrase, “Nothing is certain but death and taxes,” clearly hadn’t a clue of another of life’s immutable pairings:  histone proteins and DNA.

Histones are the chief protein components of chromatin — the protein/DNA combo of which chromosomes are made — and they act as a scaffold to allow the packaging of DNA into a condensed form that fits inside the nucleus of a cell. As the DNA interacts with histones and with metabolic signals from within the cell, these proteins help regulate gene expression.

But how does the histone component of this dynamic duo get started in the first place?  The answer, according to new research from UNC,  appears in [a] FLASH.

This protein is already shown to play a role in initiating apoptosis, or the normal process of programmed cell death, and is now the latest key player in the molecular dance essential for DNA replication within cells.

According to senior study author Zbigniew Dominski, Ph.D., associate professor of biochemistry and biophysics, the new study demonstrates that FLASH is  required for the proper synthesis of histone messenger RNA, which gives rise to histone proteins.

“FLASH is crucial for the production of histone messenger RNA, without which the cell can’t make the histone proteins around which DNA is packaged,” says Dominski. “Our study suggests for the first time that a potential link exists between the processes of histone messenger RNA formation and apoptosis.”

The research is described in the October 23rd issue of the journal Molecular Cell.

For the study, Dominski adapted a laboratory system that reproduces in the test tube what normally occurs in the cell when FLASH participates in the biochemical cleavage event that results in mature histone messenger RNA. This enabled his team to explore what might occur when FLASH was added or removed.

“We could then figure out exactly what portion of FLASH would restore the protein’s function in generating histone mRNAs and remarkably, only the first 100 or so amino acids are required.  The remaining 2,000 amino acids of this large protein likely control other processes in the cell, including apoptosis and DNA replication” he explained.

Co-author William F. Marzluff, Ph.D., is Distinguished Professor of biochemistry & biophysics. He notes that FLASH is the first component found in this protein complex that integrates or initiates many cellular functions — DNA replication, apoptosis, histone production.  “Having this small piece of the puzzle makes it a lot easier to identify others.”

Except for a certain somebody who originally paired the certainty of death and taxes.

Les Lang


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