A protein complex involved in almost every step of the regulation control of gene expression in cells has now also been shown to play a central role in clearing potential traffic jams in the production of RNA.
The RNA polymerase II (RNAPII) enzyme, which produces RNA from a DNA template, may become stuck due to damage to the DNA template, and these jams must be cleared to restore gene expression and normal cell function. New research shows that the master regulator complex "Ccr4-Not" performs this task and associates with RNAPII during the transcription of RNA from DNA and labeling RNAPII for degradation when solidified, allowing the DNA to being repaired and normal cell function
A paper describing Penn State researchers' research is displayed online in the journal Genes & Development on April 4, 2019. "Normal cellular functions depend on what is sometimes called "central biology dogma," said Joseph C. Reese, professor of biochemistry and molecular biology, and a member of the Center for Eukaryotic Gene Regulation at Penn State. "Gene in DNA is transcribed into RNA which in turn is converted into function. This is a highly orchestrated process and the precise control of gene expression and protein turnover determines cell functions.
"The Ccr4-Non complex is involved in almost every step of this process from start to finish. Our new research shows that this complex has an extra feature that helps maintain normal cellular function when something goes wrong during During the transcription of RNA from DNA, RNAPII itself is a large complex consisting of multiple protein subunits traveling along the DNA strand that reads the ATCG sequence and produces a complementary strand of RNA. If RNAPII encounters DNA damage that may be caused by UV radiation and other sources, it may become stuck and prevent subsequent polymerases from completing transcription of the gene, similar to how a stall car prevents traffic behind it from flowing. If this paper jam cannot be cleared, several RNAPIIs that transcribe the same gene may begin to recover in a kind of traffic jam that prevents the DNA from being repaired and inhibits cell function.  "Clearing fixed RNAPII is an important process for normal cell function," Reese said. "Errors in this pathway have been associated with a number of d iseas and human syndromes, such as the Cockayne syndrome – a neurodegenerative disorder that results in growth defects, neurological developmental defects and sensitivity to UV light."
The researchers used genetic methods and reconstitution chemistry – a method by which purified components in a cellular process can be added, taken away and mixed in a precisely controlled manner to identify exactly how they work – to show that Ccr4-Non recruits factors that mark RNAPII with a small signal molecule called ubiquitin. Attachment of ubiquitin to RNAPII triggers other cellular components to degrade the enzyme, clearing jam.
"Previous studies had implicated Ccr4-Not in helping cells cope with DNA damage," Reese said. "Mutating members of the Ccr4-Non complex make cells more sensitive to agents that damage the genome, but because Ccr4-Not is involved in so many aspects of gene regulation, it was not clear until now what the precise role was. Not recruiting the destruction machines for RNAPII was a surprising result, and suggests it acts as a drawn truck to remove traffic jams throughout the genome. "
Gene transcription machines limit DNA movements, the study suggests
Unjamming the genome after DNA damage: A re-regulating multi-tool has another function (2019, April 5)
April 6, 2019
This document is subject to copyright. Besides any fair trade for private study or research, no
part can be reproduced without written permission. The content is for informational purposes only.