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Regulating DNA Repair Mechanisms

Every once in a while an article comes out on a new DNA repair mechanism or a new feature of a known DNA repair mechanism. There are so many complexities behind DNA repair and there is still more to uncover. Last October, a review article came out in Molecular Cell on regulatory factors for DNA repair mechanisms (Molecular Cell 40(2), October 22, 2010, 179-204). Basically, DNA repair mechanisms are very powerful because they can often replace or remove nucleotide bases. So these powerful mechanisms need something to make sure they do their job properly and not destroy the whole genome in the process. That is where regulators come in. If DNA repair mechanisms are medics flying out to the damaged site, then the regulators would be the control tower that finds the sites, guides the planes, and tells them when to get to work and when to retreat.

From the article:

DNA repair is carried out by a plethora of enzymatic activities that chemically modify DNA to repair DNA damage, including nucleases, helicases, polymerases, topoisomerases, recombinases, ligases, glycosylases, demethylases, kinases, and phosphateases. These repair tools must be precisely regulated, because each in its own right can wreak havoc on the integrity of DNA if misused or allowed to access DNA at the inappropriate time or place.

The DNA repair mechanisms themselves are fascinating from a design perspective. The list above includes ten different tools (more like high powered machines) that the cell has available for DNA repair, but what is even more compelling from a design perspective is the regulation of the repair mechanisms. Because of the power of the repair mechanisms, there are regulators in place to recruit the right repair mechanism, lead it to the damaged spot, activate the repair mechanism, and “coordinate the choice of the pathways to employ for efficient DNA repair.” The article refers to it as a “choreographed” response system. It sounds like a control tower or central command.
These regulatory mechanisms are called DDR for “DNA damage response” and are described as a “signal transduction pathway that senses DNA damage and replication stress and sets in motion a choreographed response to protect the cell and ameliorate the threat to the organism.” The review article catalogues in fascinating detail some common types of DNA damage and the various response mechanisms and repair mechanisms that they recruit to fix this type of damage. The description of this process is remarkably complex and detailed. What is striking is just how precise these DDRs are. The timing, the order, the precision are all important because if the DDR malfunctions in any one of these, then cell death could occur.
To get an idea of just the first layer of complexity in these systems, let’s assume there is some damage to DNA, such as a single-strand break. Here is the process that would happen:

  1. DNA damage is detected by sensor proteins: PAR activation (PAR structures are described as “platforms that recruit factors for DNA repair.” PAR activation occurs within seconds of damage detection. PARP 1 and PARP2 are activated by single strand breaks and double strand breaks. They catalyze the addition of poly (ADP-ribose) chains on proteins to recruit DDR factors to chromatin at those breaks.)
  2. ATM activation (ATM and ATR kinases as seem to send out the distress signal to recruit the right DNA repair proteins. They do this by phosphorylating mediator proteins.)
  3. MDCI recruitment (This induces a signaling cascade.)
  4. RNF8 recruitment
  5. RNFi68 recruitment
  6. BRCA1 and 53BP1 recruitment
  7. (Numbers 4-6 are particular proteins that are recruited in a very specific order to do specific activities to repair a single strand break.)

  8. Based on certain factors such as timing and order of recruitment, any one of these results may happen: the cell cycle could be delayed, DNA could be repaired by replacing nucleotide bases, differentiation may be halted (senescence), cell death (apoptosis), transcription and splicing controls, or metabolic regulation.

Within each of these steps are sub-steps that have been omitted for clarity. However, it is through some of these sub-steps that the repair decisions are mediated. Not only that, but this is just one DDR for a particular type of DNA damage. Double strand breaks, for example, have four different repair pathways. All of this is just the regulation of the DNA repair mechanisms, not the actual repair itself.
Such precision, regulation, and coordination seem to point towards a designed mechanism. We see regulatory processes in computer programming and in engineering when the programmer or engineer wants to ensure the integrity of a vital part of his system. Any of us who have had to deal with operating system problems understands that there have to be checks, and double checks whenever you are upgrading or adding software. Without these regulators, the whole system is corrupted. Certainly DNA plays a vital role in the cells, much like an operating system. Ensuring its replication integrity is key to the survival of the organism.
Defects within the DDR system can be catastrophic to the health of the organism:

The central role of the DDR in human physiology is indicated by the broad spectrum of defects displayed by individuals carrying mutations in DDR genes. DDR genetic syndromes primarily affect the homeostasis of the nervous, immune, and reproductive systems and can lead to premature aging or cancer predisposition.

If defects in the DDR system affect survival and reproduction, then from a Darwinian perspective, the DDR must have evolved at the same time as the DNA repair mechanisms. And because the DDR system is a pathway that functions holistically with the DNA repair mechanisms, it is difficult to argue for a step-by-step building up of this process particularly because a defect can result in sterility, which means intermediate progress cannot be passed on.
The review article concludes by stating “…the coordination of DNA repair processes plays a critical role in allowing the proper development and survival of organisms.” If this is the case and the role of the DDR is vital for the cell, then the question we should be asking is: How does the cell evolve a complex, precise pathway such as DDR to communicate information to the DNA repair mechanism? These DNA damage repair regulators are very precise, coordinated pathways that “know” how to send information to the repair mechanism. The mechanisms for DNA repair are a fascinating field of research with frequent new discoveries, including how these repair mechanisms are regulated. However, it seems that to explain the origin of these systems, scientists will need to expand their framework, because the Darwinian step-by-step process of natural selection acting on random mutations does not currently have the explanatory capacity for this type of system.

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