Scientists discover molecular 'policeman'

Weizmann team identifies mechanism which keeps tabs on cancer-causing mutations.

cancer molecules 88 (photo credit: )
cancer molecules 88
(photo credit: )
Researchers at the Weizmann Institute of Science have discovered a mechanism that acts like a policeman to minimize genetic mutations - genetic mistakes in the DNA sequence during cell division - that can cause cancer. The fact that mutations are harmful has been known for some time - the more mutations in a 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. A preliminary answer to the question of how the body keeps these processes in check, thus preventing a sharp rise in the risk of cancer, has been found by a team of researchers. Prof. Zvi Livneh and research student Sharon Avkin, along with research student Leanne Toube, Dr. Ziv Sevilya of the biological chemistry department, Prof. Moshe Oren of the molecular cell biology department, and two American colleagues recently published the results of their study in the scientific journal Molecular Cell. The researchers hope that their discovery will eventually help in the clinical fight against cancer. The team at the Rehovot institute discovered a security mechanism of two proteins that prevent the proliferation of mutations and manage to help the body's cells maintain a crucial balance, allowing them to divide and multiply while keeping the mutation rate to a minimum. The instruments of DNA copying (which takes place just prior to cell division) are members of a family of enzymes called DNA polymerase. This travels along one strand of the double-stranded molecule, reading each bit of genetic material and copying as it goes, 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 10 different "careless" enzymes, although this may seem paradoxical. Intuitively, "more-careless enzymes" should mean more mutations. But each of these enzymes is tailored to deal with certain specific types of DNA damage. This specialization is what keeps the level of mutation 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. The security 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. Named "Molecule of the Year" several years ago by the prestigious journal Science, p53 is well known for its central role in controlling 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 (discovered years ago by Israeli Chemistry Nobel Prize laureates Prof. Avram Hershko and Prof. Aaron Ciechanover of the Technion-Israel Institute of Technology, and an American colleague) attaches to the clamp. Ubiquitin, in this case, serves to anchor replacement DNA polymerase molecules - "careless ones" - to the clamp. Then 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.