A multi-tool genetic regulation has yet another function

A protein complex involved in almost all steps of regulatory control of gene expression in cells now plays a key role in removing potential bottlenecks in RNA production.

RNA polymerase II (RNAPII) – the enzyme that produces RNA from a DNA template – can remain stuck due to the damage of the matrix of DNA. These jams must be removed to restore gene expression and normal cell function. New research shows that the main regulatory complex, "Ccr4-Not", accomplishes this task by associating with RNAPII when transcribing RNA from DNA and labeling RNAPII for degradation when it gets stuck, allowing DNA to be repaired and normal CV function.

An article describing research conducted by Penn State scientists appears online in the newspaper Genes and development 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 Eukaryotic Gene Regulation. at Penn State. "The DNA genes are transcribed into RNA, which in turn is translated into proteins, which provide the function of the cell.This is a highly orchestrated process. gene expression and protein turnover determine cellular functions.

"The Ccr4-Not complex is involved in almost every step of this process, from start to finish, and our new research shows that this complex has an additional function that helps maintain normal cell function when there is a problem with transcription. . "

During the transcription of RNA from DNA, RNAPII, which itself is a large complex composed of several protein subunits, traverses the strand of DNA reading sequence ATCG and producing a complementary strand of RNA. If the RNAPII encounters damage to DNA, which can be caused by UV rays and other sources, it can get stuck and prevent the remaining polymerases from completing the transcription of the gene, in the same way as A blocked car prevents the traffic behind it from flowing. If this bottling can not be eliminated, multiple RNAPIIs transcribing the same gene can accumulate in a sort of bottling, thus preventing DNA repair and impeding cell function.

"The removal of blocked RNAPII is an essential process for normal cell function," said Reese. "The defects of this pathway have been associated with a number of human diseases and syndromes, such as Cockayne's syndrome, a neurodegenerative disease that causes growth retardation, neurodevelopmental abnormalities and sensitivity to UV light. "

The researchers used genetic methods and biochemistry reconstitution, a method to add, collect and mix in a perfectly controlled manner purified components of a cellular process to determine their mode of operation, to demonstrate that Ccr4 -Not recruits RNAPII's key factors with a small signaling molecule called ubiquitin. Fixing ubiquitin on RNAPII triggers the degradation of the enzyme by other cellular components, thus eliminating blockage.

"Previous studies had involved Ccr4-Not in helping cells to cope with DNA damage," said Reese. "The mutation of the members of the Ccr4-Not complex makes cells more sensitive to agents that damage the genome, but since Ccr4-Not is involved in many aspects of gene regulation, it was unclear until now which was his precise role.Ccr4 -No recruited the RNAPII destruction material was a surprising result, and suggests that it acts as a tow truck to remove traffic jams in the genome. "

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