Gene activation governed by machines

How 'molecular machines' kick start gene activation revealed

Quote:

How 'molecular machines' inside cells swing into action to activate genes at different times in a cell's life is revealed today (6 November) in new research published in Molecular Cell. Genes are made of double stranded DNA molecules containing the coded information an organism's cells need to produce proteins. The DNA double strands need to be 'melted out' and separated in order for the code to be accessed. Once accessed, the genetic codes are converted to messenger RNAs (mRNA) which are used to make proteins. Cells need to produce particular proteins at different times in their lives, to help them respond and adapt to changes in their environment.

The "melting out" process is carried out by helicases which is part of the replisome. Exquisitely controlled.
Helicases are also known to be ring-shaped motor proteins, typically hexamers and separate double-stranded DNA into single-stranded templates for the replication machinery. Replication occurs at about 1000 base pairs per second due to the highly efficient combination of sliding clamps and the polymerases. Thus, helicases need to unwind DNA at at least that speed. Unwinding DNA too slowly and the replication machinery might break down . Unwind the DNA too fast or untimely and harmful mutations might occur as single-stranded DNA is prone to degradation and cytosine deamination. The speed at which helicase unwinds DNA is no accident though, as it is intrinsically controlled. As helicase is bound to the lagging strand, it unwinds the leading strand in a separate direction. Applying a pulling force on the leading strand leads to a 7-fold increase in the speed of DNA unwinding by helicase. The highly efficient DNA polymerase/sliding clamp combination provides this controlling force on the leading strand. This forms a robust unwinding/polymerization interaction whereby polymerization controls and prevents unwanted DNA unwinding.

Quote:

The new study outlines exactly how a molecular machine called RNA polymerase, which reads the DNA code and synthesizes mRNA, is kickstarted by specialised activator proteins. The scientists have discovered that RNA polymerase uses a tightly regulated internal blocking system that prevents genes from being activated when they are not needed. Using electron microscopy to look at the inner workings of bacterial cells, the researchers discovered that the DNA strand-separating process is kickstarted when RNA polymerase is modified by an activator protein, which the cell sends to the site of the gene that needs to be switched on. This activator protein jump-starts the RNA polymerase machine by removing a plug which blocks the DNA's entrance to the machine. The activator protein also causes the DNA strands to shift position so that the DNA lines up with the entrance to the RNA polymerase. Once these two movements have occurred and the DNA strands are in position, the RNA polymerase machine gets to work melting them out, so that the information they contain can be processed to produce mRNA, and ultimately allow production of proteins. Professor Xiaodong Zhang, lead author of the paper from the Department of Life Sciences at Imperial College London, explains the significance of the team's findings, saying: "Understanding how the RNA polymerase gene transcription 'machine' is activated, and how it is stalled from working when it is not needed, gives us a better insight than ever before into the inner workings of cells, and the complex processes that occur to facilitate the carefully regulated production of proteins." Professor Martin Buck, Head of Imperial's Division of Biology and one of the paper's co-authors, adds that understanding how this process works in bacteria cells is of particular interest, because it is this gene transcription and protein production process which allows bacterial cells to adapt, respond and thrive despite changes in their environment: "In other words, this is the process that occurs inside bacteria that makes them so good at survival. Many bacteria cause infection and disease in humans, and are hard to defeat. Bacterial RNA polymerase is a proven target for antibiotics such as rifampicin, against which many bacteria have become resistant. Insights gained form our research will now provide opportunities and strategies for the design of novel antibacterial compounds," he concludes

So machines govern the activity of gene expression, and machines are governed by gene expression through a reasonably optimal genetic code mmmm....