A Stalled RNA Polymerase Can Restart

KEY CONCEPTS
- Sequences in the DNA can cause the RNA polymerase to pause.
- An arrested RNA polymerase can restart transcription by cleaving the RNA transcript to generate a new 3′ end.
RNA polymerase must be able to handle situations when transcription elongation is blocked or sequences cause the polymerase to pause. Blockage can happen, for example, when DNA is damaged. A model system for such situations is provided by arresting elongation in vitro by omitting one of the necessary precursor nucleotides, allowing fraying of the end of the RNA. Any event that causes misalignment of the 3′ terminus of the RNA with the active site results in the same problem, though: Something is needed to reposition the 3′–OH of the nascent RNA with the active site so that it can undergo attack from the next NTP and phosphodiester bond formation. Realignment is accomplished by cleavage of the RNA to place the terminus in the right location for addition of further bases.
Although the cleavage activity is intrinsic to RNA polymerase itself, it is stimulated greatly by accessory factors that are ubiquitous in the three biological kingdoms. Two such factors are present in E. coli, GreA and GreB, and eukaryotic RNA polymerase II uses TF S for the same purpose. TF_II S displays little similarity in sequence or structure to the Gre factors, but it binds to the same part of the enzyme, the RNA polymerase secondary channel (pore). The Gre factors/TF_II S enable the polymerase to cleave a few ribonucleotides from the 3′ terminus of the RNA product, thereby allowing the catalytic site of RNA polymerase to be realigned with the 3′–OH. Each of the factors inserts a narrow protein domain (in TF_IIS this is a zinc ribbon, in the bacterial enzyme it is a coiled coil) deep into RNA polymerase, approaching very close to the catalytic center. Two acidic amino acids at the tip of the factor approach the primary catalytic magnesium ion in the active site, allowing a second magnesium ion to enter and convert the catalytic site to turn into a ribonuclease.
In addition to damaged DNA, certain sequences have the intrinsic ability to cause the polymerase to pause. Prolonged pausing may lead to termination, discussed below. An example of an E. coli pause-inducing sequence is GxxxxxxxxCG (where x is any base). Pausing may be regulatory in that transcription and translation of the mRNA can be coordinated.
In summary, the elongating RNA polymerase has the ability to unwind and rewind DNA, to keep hold of the separated strands of DNA as well as the RNA product, to catalyze the addition of ribonucleotides to the growing RNA chain, to monitor the progress of this reaction, and—with the assistance of an accessory factor or two—to fix problems that occur by cleaving off a few nucleotides of the RNA product and restarting RNA synthesis.

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