Scientists discover molecular security mechanism for keeping gene mutations in check

May 8 2006

Everyone knows mutations - genetic mistakes in DNA, the material of heredity - are bad: The more mutations in the cell's DNA, the higher the risk of cancer developing.

But in the last few years it has become clear that the very processes that generate mutations, if they take place at a relatively low frequency, can actually protect us from cancer.

How does the body know how to keep these processes in check, making sure they don't rocket out of control, causing a sharp rise in our cancer risk? A preliminary answer to this question has come out of research carried out by Prof. Zvi Livneh and research student Sharon Avkin, along with research student Leanne Toube and Dr. Ziv Sevilya of the Biological Chemistry Department, and Prof. Moshe Oren of the Molecular Cell Biology Department, along with two American colleagues. The results of their study appeared recently in the scientific journal Molecular Cell.

The instruments of DNA copying (which takes place prior to cell division) are members of a family of enzymes called DNA polymerase. DNA polymerase travels along one strand of the double stranded molecule, reading each bit of genetic material and copying as it goes along, to create new DNA that will be passed on to the daughter cell at cell division. This enzyme can be a stickler for accuracy - if it runs into damage from radiation or exposure to harmful substances on the DNA strand, it can stop in its tracks, unable to continue copying. A stoppage of this sort spells death for the cell. But not all damage to DNA is critical and, to avoid the wholesale death of cells, a second type of DNA polymerase, one that is more "careless" and can improvise when it hits a snag, evolved in the cell. "Error-prone DNA repair," as it's called, is based on a compromise: The cell lives, but at the price of allowing genetic mutations to be carried over in cell division.

The body's solution to minimizing mutations is to have no fewer than ten different "careless" enzymes. Although this may seem paradoxical - intuitively, more careless enzymes should mean more mutations - each of these enzymes is tailored to deal with certain specifics types of DNA damage. This specialization is what keeps the level of mutation, and thus the cancer risk, low. But the existence of this variety of specialist enzymes implies precise regulation of the system - otherwise copying by the careless enzymes might get out of control and lead to an unhealthy proliferation of mutations.

Prof. Livneh and his team recently discovered a security mechanism that prevents such proliferation of mutations. This mechanism allows the right enzyme to go to work at the right time, and only when it's needed. The main components in this system are the proteins p53 and p21. p53, named "molecule of the year" several years ago by Science, is well known for its central role in reining in cancer processes in the cell. In this case, the proteins seem to act as supervisors, taming the careless enzymes and keeping them in careful check. The scientists' research showed that if the functioning of p53 or its relative, p21, is harmed, the activities of the careless enzymes can go into overdrive, leading to more mutations.

The actual mechanism works with a sort of molecular clamp that holds the DNA copying enzyme onto the strand of DNA. When the enzyme encounters DNA damage, a small molecule called ubiquitin attaches to the clamp. The ubiquitin, in this case, serves to anchor replacement DNA polymerase molecules - careless ones - to the clamp. p53 enters the picture when it is alerted to the damage and causes p21 to be created. The p21 then acts as a sort of facilitator, helping to fasten the proper ubiquitin in place and clearing stalled DNA polymerase out of the way so its replacement can get to work. Thus, these two proteins manage to help the body's cells maintain a crucial balance, allowing them to divide and multiply while keeping the mutation rate, and therefore the cancer risk, to a minimum.