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Developmental Biology - Genetics

Unjamming DNA Log Jams

Ccr4-Not is a 'multi-tool' involved in nearly every step of controlling gene function...

During transcription RNAPII — a large complex of multiple protein subunits — travels along the DNA strand reading each ATCG sequence and producing a complementary RNA strand. If RNAPII encounters DNA damage, caused by UV radiation or other sources, it can get stuck and not complete transcription. Similar to how a stalled car prevents traffic behind it from flowing. If this jam is not quickly cleared, multiple RNAPIIs transcribing the same gene to make other unique proteins, begin to pile up preventing DNA repair and hampering cell function.

"Clearing stuck RNAPII is an essential process in normal cell function," explains John Reese PhD, author on the paper and professor of biochemistry and molecular biology and associate head of research and faculty development at The Pennsylvania State University, USA. "Defects in this pathway have been associated with a number of diseases and syndromes, such as Cockayne syndrome — a neurodegenerative disorder that results in growth failure, neurological developmental defects and sensitivity to UV light."
Researchers use genetic methods and reconstitution biochemistry — meaning purified components of a cell process can be added, taken away, and mixed in a precise manner allowing exact identification of how they function — and revealed Ccr4-Not recruits factors that mark RNAPII with a small signaling molecule called ubiquitin. Attaching ubiquitin to RNAPII triggers other cell components to degrade RNAPII (an enzyme) clearing the jam.

"Previous studies have implicated Ccr4-Not in helping cells cope with DNA damage," adds Reese. "Mutating members of the Ccr4-Not complex makes cells more sensitive to agents that damage the genome. But, as Ccr4-Not is involved in so many aspects of gene regulation, it wasn't clear until now what precisely it does. The fact that Ccr4-Not recruits destruction machinery to RNAPII is a surprising result, suggesting it acts as a tow truck to remove traffic jams throughout the genome."

The paper describing the research by Penn State scientists appears online in the journal Genes & Development on April 4, 2019.
"Normal cell functions rely on what is sometimes called the 'central dogma' of biology: Genes in DNA are transcribed into RNA, which is translated into protein that carrys out cell functions. This is a highly orchestrated process — the precise control of gene expression and protein turnover determines all cell functions. The Ccr4-Not complex is involved in nearly every step of this process — from start to finish. Now our research shows this complex has an added function — helping maintain normal cell function when something goes wrong in transcription."

Joseph C. Reese PhD, professor of biochemistry and molecular biology; member of the Center for Eukaryotic Gene Regulation at Pennsylvania State College, PA, USA.

The Ccr4–Not complex regulates essentially every aspect of gene expression, from mRNA synthesis to protein destruction. The Not4 subunit of the complex contains an E3 RING domain and targets proteins for ubiquitin-dependent proteolysis. Ccr4–Not associates with elongating RNA polymerase II (RNAPII), which raises the possibility that it controls the degradation of elongation complex components. Here, we demonstrate that Ccr4–Not controls the ubiquitylation and turnover of Rpb1, the largest subunit of RNAPII, during transcription arrest. Deleting NOT4 or mutating its RING domain strongly reduced the DNA damage-dependent ubiquitylation and destruction of Rpb1. Surprisingly, in vitro ubiquitylation assays indicate that Ccr4–Not does not directly ubiquitylate Rpb1 but instead promotes Rpb1 ubiquitylation by the HECT domain-containing ligase Rsp5. Genetic analyses suggest that Ccr4–Not acts upstream of RSP5, where it acts to initiate the destruction process. Ccr4–Not binds Rsp5 and forms a ternary complex with it and the RNAPII elongation complex. Analysis of mutant Ccr4–Not lacking the RING domain of Not4 suggests that it both recruits Rsp5 and delivers the E2 Ubc4/5 to RNAPII. Our work reveals a previously unknown function of Ccr4–Not and identifies an essential new regulator of RNAPII turnover during genotoxic stress.

Haoyang Jiang, Marley Wolgast, Laura M. Beebe and Joseph C. Reese.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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Apr 9 2019   Fetal Timeline   Maternal Timeline   News  

Ccr4–Not initiates destruction of RNAPII (black) which is obstructing DNA strand (gold) being read, by recruiting ubiquitin to degrade RNAPII and maintain cell function. Image: Pixabay.

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