A multi-regulatory gene tool has another function.



Unclogging the genome after damaging DNA

Ccr4-No to the rescue. A) The Ccr4-Not complex badociates with RNA polymerase II (RNAPII) as it travels along a strand of DNA-producing RNA. B) When RNAPII is clogged due to DNA damage, Ccr4-No recruits factors that label RNAPII with a small signaling molecule called ubiquitin. C) Ubiquity triggers the degradation of RNAPII, allowing the DNA repair enzymes to repair the damage and restore gene expression. Credit: Reese Laboratory, Penn State

It has now been shown that a protein complex involved in almost all steps in the regulatory control of gene expression in cells also plays a key role in eliminating potential traffic jams in RNA production.

RNA polymerase II (RNAPII), the enzyme that produces RNA from a DNA template, can get stuck due to damage to the DNA template, and these clogs must be removed to restore gene expression and normal cell function. New research shows that the master regulatory complex, "Ccr4-Not," performs this task, badociates with RNAPII during the transcription of DNA RNA and marks RNAPII for degradation when it is clogged, allowing the DNA to be repaired and the normal cellular function curriculum.

An article describing research conducted by Penn State scientists appears online in the journal Genes and Development on April 4, 2019.

"Normal cellular functions are based on what is sometimes called the 'central dogma of biology,'" said Joseph C. Reese, professor of biochemistry and molecular biology and a member of the Center for Genetic Regulation. eukaryotes at Penn State. "The genes in the DNA are transcribed into RNA, which in turn is translated into proteins, which play the role of the cell.This is a highly orchestrated process and the precise control of gene expression and protein turnover determines the functions cell phones.

"The Ccr4-Not complex is involved in almost every step of this process, from start to finish." Our new research shows that this complex has an additional function that helps maintain normal cell function when something fails during transcription.

During transcription of RNA from DNA, RNAPII, itself a large complex composed of multiple protein subunits, travels along the DNA strand reading the ATCG sequence and producing a complementary strand of RNA. If RNAPII finds DNA damage, which can be caused by UV radiation and other sources, it can clog and prevent lost polymerases from completing gene transcription, similar to how a stopped car prevents traffic from flowing behind it. the. If this clogging can not be eliminated, several RNAPII that transcribe the same gene can begin to accumulate in a kind of traffic jam that prevents DNA repair and hinder cell function.

"The removal of clogged RNAPII is an essential process for normal cell function," Reese said. "Defects in this pathway have been badociated with a series of human diseases and syndromes, such as Cockayne syndrome, a neurodegenerative disorder that causes growth failure, neurodevelopmental defects and sensitivity to UV light."

The researchers used genetic methods and biochemical reconstitution, a method by which purified components of a cellular process can be added, removed and mixed in a precisely controlled manner to identify exactly how they work, to show that Ccr4-Not resorts to factors that they mark RNAPII with a small signaling molecule called ubiquitin. The binding of ubiquitin to RNAPII triggers other cellular components to degrade the enzyme, eliminating clogging.

"Previous studies had implicated Ccr4-Not in helping cells deal with DNA damage," Reese said. "The mutant members of the Ccr4-Not complex make the cells more sensitive to the agents that damage the genome, but because Ccr4-Not is involved in so many aspects of gene regulation, it was not yet clear what their function was The fact that Ccr4-No recruited the destruction machinery for RNAPII was a surprising result, and suggests that it acts as a crane to eliminate traffic jams throughout the genome. "


One study suggests that the genetic transcription machinery restricts DNA movements


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Pennsylvania State University


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Disbademble the genome after DNA damage: a multi-regulatory gene tool has another function (2019, April 5)
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