Every coin has two sides. These things, it turns out, are also true when it comes to mutations
Weizmann Institute
Every coin has two sides. These things, it turns out, are also true when it comes to mutations, which are genetic errors in the hereditary material, the DNA. The accepted concept is that as the mutations multiply, the risk of developing cancer increases. However, in recent years it has become clear that mutation-causing processes, which occur at a low dose, actually protect us from the development of cancer. How does the body know how to ensure that the processes that cause the mutations will take place to the right extent, and that they will not get out of control, and will not cause a sharp increase in the risk of cancer? A preliminary answer to this question emerges from research recently carried out by Prof. Zvi Livna, research students Sharon Avkin and Liane Taub, and Dr. Ziv Seville from the Department of Biological Chemistry, Prof. Moshe Oren from the Department of Molecular Cell Biology, and two researchers from the USA. This study was published today (May 4, 2006) in the scientific journal Molecular Cell.
The process of reproduction of the genetic material, in the process of division of living cells, is based on a family of enzymes of the DNA polymerase type. This enzyme "travels" on one of the strands of the genetic material, "reads" it and produces a copy based on it that goes into the new cell that develops from the original cell. When there is chemical damage on the DNA strand (as a result of radiation or exposure to various harmful substances), an enzyme with a good level of accuracy stops and cannot continue on its way. Such a stop causes the cell to die. Since it is clear that not every DNA damage justifies such an extreme step, relatively "negligent" enzymes have also evolved in the body, which are able to "improvise" and continue the process even when they encounter damage. This process, known as "error-prone DNA repair", is a process of compromise: it allows the cell to live, but at the cost of a certain generation of mutations that inevitably arise as a result of the need to replicate the DNA segment, where the damage disrupted the information the genetic In order to minimize the number of mutations, no less than ten "negligent" DNA duplicating enzymes have been developed in the body. At first glance this seems paradoxical, since the proliferation of such enzymes may lead to the undesired result of an increase in the rate of mutations. But in fact, each sloppy enzyme has the expertise to relatively accurately overcome certain types of DNA damage. When each enzyme treats only the damage it is intended for, the result is a relatively low level of mutations, and therefore there is a low risk of developing cancer. It is clear that such a mechanism requires a strict control system that will prevent unrestrained activity of the "negligent" replicating enzymes, which may cause an unwanted proliferation of mutations.
Prof. Livna and the members of his research group recently discovered the security mechanism that prevents excessive outbreaks of mutations. This mechanism is based on a kind of strict work arrangement between the "negligent" DNA-replicating enzymes, so that each of them only works when its special properties are really needed, which ultimately minimizes the rate of mutations.
The main players in this security mechanism are the proteins p53 and p21. The p53 protein was previously known as the "guardian of the genome", and was even named "molecule of the year" by the scientific journal "Science". This protein plays a central role in inhibiting cancerous processes in the body and in making the "decision" when the genetic damage caused to the cell can be repaired, and when it is so severe that to prevent the development of a cancerous tumor it is better to cause the death of the individual cell. Prof. Livna's research reveals that p53 and one of its relatives, p21, are security factors that restrain the rate of activity and the generation of mutations of the enzymes that replicate DNA. When the function of one of these regulatory proteins is damaged, the body's oversight of the genetic replication processes decreases, which causes the unrestrained activity of the "negligent" enzymes, and leads to the formation of more mutations and an increased risk of developing cancer.
How do they do it? It turns out that the enzyme that replicates the DNA is attached to the strand of the genetic material on which it moves by means of a kind of "molecular latch". When this enzyme encounters DNA damage, the protein ubiquitin clings to its "molecular catch". This protein usually "marks" proteins destined for degradation, but in this case it constitutes a kind of "anchor" to which the replacing, more "negligent" replicating enzymes bind. The p53 protein activates the creation of the p21 protein, and it binds first to the "molecular catch", and accelerates the binding of ubiquitin to it. It also increases and removes from the way the replicating enzyme that has failed, thereby preparing the area for a faster and more efficient uptake of ubiquitin, to which the replacement enzyme is then bound. This is how p21 regulates the replication process of the genetic material while maintaining a balance between the body's need to keep the cells alive (even with a certain concession and being satisfied with an imperfect level of accuracy), and preventing the formation of too large a quantity of mutations, which could increase to an unwanted degree the The risk of developing cancerous tumors.
