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A Look at the Quality Control System in the Protein Factory

factory floor.jpg

It's been a while -- too long! -- since ENV reported on a new discovery from the study of the highly complicated DNA damage response system. (See here for a background article on DNA damage response systems.)

DNA is an information carrier that, through the transcription of its sequence into RNA and the translation of RNA, gives the instructions for building a protein. With its information-carrying capacity, DNA is an excellent example of a cellular structure that has all of the features you would expect in a designed artifact.

However, nucleotide translation is only the first layer of complexity in this intricate system. If DNA doing its normal job isn't complicated enough, consider what happens when damage to the DNA molecule occurs. The DNA damage response (DDR) system is like a cellular special ops force. The moment such damage is detected, an intricate network of communication and recruitment launches into action. If the cellular process for making proteins were a factory, this would be the most advanced quality-control system ever designed.

A new study in Molecular Cell reports finding hundreds of nuclear and nonnuclear DNA damage response-regulated modification sites that were not previously known to be involved in the DDR process (Beli et al., "Proteomic Investigations Reveal a Role for RNA Processing Factor THRAP3 in the DNA Damage Response," doi:10.1016/j.molcel.2012.01.026). The authors looked at phosphorylation and acetylation, two chemical processes that act as signals for the DDR system. Their studies of phosphorylation, in particular, revealed additional layers of complexity and recruitment of proteins that had not already been considered part of the DDR system.

Phosphorylation, occuring after translation, attaches a phosphate group to particular amino acids on proteins. Phosphorylation is involved in several protein activities, and has been used as a marker in cancer research. Entire databases are available cataloging post-translational phosphate modification (see here for an example).

The current study, while adding to the body of literature in this field, also discusses some important features bearing on the complexity and inter-connectivity of the DDR system. The complexity of these systems and internal networking seem to imply the system is akin to a complex factory or work of engineering, not something that was the result of a Darwinian step-by-step process.

One level of complexity found is reflected in the apparent coordination between phosphorylation and acetylation. When DNA damage occurs, and is transcribed then translated, the resultant protein is "flagged" by chemical markers. These markers are phosphates and acetyl groups. Phosphorylation is much more common and more highly regulated than acetylation. However the authors comment:

Collectively, our proteomic screen demonstrates that all three modes of regulation -- phosphorylation, acetylation, and protein expression changes -- act in a coordinated manner to establish the cellular DDR.
A highly coordinated system poses problems for evolutionary theory because it requires bringing together all of the right pieces, at the right time, in the right place, to do a specific job. The development of such a level of precision is difficult to account for by reference to an exclusively Darwinian mechanism.

The authors also identified many DNA damage-induced phosphorylations on RNA processing factors. Many of these RNA processing factors had not been known to be associated with the DDR system.

One specific factor that the authors studied was THRAP3 phosphorylation and how it is involved in DNA damage repair. THRAP3 functions in RNA splicing and RNA degradation, and the authors founds that it is phosphorylated and excluded from sites of DNA damage, while a different factor, PPM1G, involved in RNA splicing regulation, is recruited at the site of DNA damage. Apparently DNA damage and RNA transcription are interconnected at this regulatory level:

Notably, we found that deleting the amino- and carboxyl-terminal regions of THRAP3 -- which are important for its role in RNA splicing and RNA degradation, respectively -- impaired THRAP3 exclusion from DNA damage regions. These findings, taken together with the fact that RNA polymerase II transcription is inhibited at flanking DSB [double strand break] sites, led us to speculate that THRAP3 exclusion was a readout of reduced transcription and processing of nascent RNA transcripts.
While other studies have shown that DNA damage results in transcription inhibition, the authors have successfully identified two factors involved in DDR that are also associated with RNA. PP1G is known for promoting pre-messenger RNA splicing, but when DNA damage occurs, PP1G is phosphorylated and is "rapidly and temporarily recruited to DNA damage sites."

THRAP3, known to be involved in RNA processing and stability, is also phosphorylated when DNA is damaged. Interestingly, the phosphorylation is reversible. It is a signal that turns on or off certain functions in PP1G and THRAP3. Something can't be a signal unless whatever is supposed to receive the signal is already set up to do so. This behavior is reminiscent of computer programming where THRAP3 and PP1G are programmed to perform one process, unless a chain of events occurs, leading to phosphorylation, which deactivates one program and activates another one.

Overall, the study gives a very detailed picture of DDR regulation, and provides additional evidence of how highly complex the system is:

In our study, treating cells with DNA-damaging agents increased phosphorylation of over 1400 sites on several hundred proteins that participate in diverse cellular functions, which highlighted the complexity of DDR-regulated signaling networks beyond the localized repair of the damaged DNA.
ENV's interest in this is, not least of all, from the engineering standpoint. The DNA damage-response system represents a marvel of intricate engineering. However, there are other reasons to analyze these systems, and considering them from a design perspective can help in framing the issue.

For one thing, cancerous cells are often the result of damage to DNA, leading to mistranslation and faulty proteins. Being able to look at where the DDR system broke down may highlight where particular cancer therapies need to focus.

In this sense, if the cell is a factory, cancer in many instances follows from a breakdown in quality control and the resulting perpetuation of one small error down the factory line. This is of course yet another respect in which intelligent design, far from being a "science stopper," may point the way to advances that other scientific paradigms seem more likely to miss.