A typo might change the whole meaning of an essay or, more likely, pass unnoticed. Add more typos, and chances are greater that the meaning will be skewed. In our cells, these “typos” are mutations – genetic mistakes in DNA, the material of heredity. If the instructions contained in the DNA become distorted through mutation, the result could be cancer. But the body can’t afford to consign every potentially cancerous cell to the bin. Just as readers might tolerate a few typos, as long as the meaning is clear, our bodies have evolved ways to ignore some mutations. In fact, scientists have begun to realize that mechanisms allowing some mutations to be carried over to the next generation of cells might be an effective strategy for preventing cancer.
How does the body decide when and where to ignore mutations? The answer begins with the steps leading up to cell division. Before a cell can divide, it needs to make an extra copy of its DNA. An enzyme called DNA polymerase travels along one strand of the double-stranded molecule, reading each bit of genetic material and copying as it goes along, creating new DNA that will be passed on to the daughter cell. 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. A second type of DNA polymerase, however, can be called in to finish the job. This enzyme is more “careless” and can improvise when it hits a snag. “Error-prone DNA repair,” as it’s called, is based on a compromise: The cell lives, but at the price of allowing the genetic mutation to be carried over in cell division.
To minimize the number of potentially harmful mutations, the body has no fewer than ten different “careless” enzymes. Although this may seem counterintuitive – more careless enzymes would seem to imply more mutations – each of these enzymes is tailored to deal with certain specific 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. The question is: What keeps copying by careless enzymes under control, so as to prevent an unhealthy proliferation of mutations?
Prof. Zvi Livneh and research student Sharon Avkin, along with research student Leanne Toube and Dr. Ziv Sevilya, all of the Biological Chemistry Department, Prof. Moshe Oren of the Molecular Cell Biology Department and two American colleagues, recently discovered a security mechanism that prevents just such proliferation. This mechanism allows the right enzyme to go to work – but only at the right time and only if it’s needed. The main components of the system are two proteins known as p53 and p21. One of the best-studied proteins around, p53 was even named “molecule of the year” by Science magazine a few years back, because of its starring role in reining in cancer processes in the cell. In the security mechanism, it seems to act as a sort of supervisor, keeping the careless enzymes in check. When the functioning of p53 or its sidekick, p21, was impaired in the team’s experiments, the activities of the careless enzymes tended to go into overdrive, and more mutations ensued.
The nuts and bolts of the mechanism include a sort of molecular clamp that holds the DNA polymerase onto the DNA strand and a small molecule called ubiquitin. When the copying enzyme encounters a problem, the ubiquitin attaches to the clamp. This small molecule, in turn, anchors one of the careless enzymes to the clamp. Meanwhile, p53 is alerted to the damage and causes p21 to be created. It is the p21 that facilitates the changeover from one to the other; it clears the stalled DNA polymerase out of the way and helps to fasten the ubiquitin in place so that the replacement enzyme can get to work. The scientists believe that by carrying out only “authorized” switches, these two molecules keep a tight rein on the number of error-prone repairs.
Carelessness, in other words, may be tolerable, but only if it’s kept in check. With the judicious use of “careless” enzymes, the body maintains its balance – allowing cells to get on with their lives, while keeping mutations to a minimum.
Prof. Zvi Livneh’s research is supported by the M.D. Moross Institute for Cancer Research; the Dr. Josef Cohn Minerva Center for Biomembrane Research; the J & R Center for Scientific Research; the Levine Institute of Applied Science; and the Flight Attendant Medical Research Institute.