A newly discovered enzyme described by Pitt researchers in a study published online Oct. 21 is believed to play a key role in maintaining the integrity of a cell’s genetic information—the basis by which the life of a cell or species is preserved—by allowing its DNA to be replicated despite discovery of a mishap on the sequence that it corrects with a new mistake.
Its sophisticated yet quick-fix tactics, employed at a most critical time, when typically damage can halt replication altogether, may save the cell from near certain death. Harnessing its unique capabilities could have implications for treating some cancers.
In the paper posted on the Web site of The EMBO Journal, an official journal of the European Molecular Biology Organization, the researchers describe how DNA polymerase Q, or POL-Q, has the exceptional ability to bypass damaged spots in the DNA sequence that are caused by a cell’s normal wear and tear or other abuses. In addition, it is the only-known enzyme that orchestrates not only one, but two steps involved in bypassing common types of DNA damage.
POL-Q is one of 15 different DNA polymerases in human cells. These specialized enzymes carry out the duplication, proofreading, and repair of DNA. DNA is a double-stranded molecule that contains genes necessary for the production of proteins, which, in turn, determine all aspects of a cell’s structure, function, and movement.
Each strand consists of nucleotides with any combination of four nitrogen-containing bases—A, T, C, and G, for short—that when in proper sequence are paired with those on the opposing, complementary strand. About 1,000 nucleotides are copied per second, and mistakes in the process are rare. Problems in the sequence sometimes arise, such as a wrong or missing base or one that is damaged. If a problem somehow evades detection, it can prevent DNA from being replicated or result in a mutation in the copied DNA.
The researchers found POL-Q’s role is to detect late-stage mishaps in the replication process, specifically those that are found at a juncture called the replication fork, just before separation of the copied parent and daughter strand takes place. Rather than stop the process altogether, which would result in the cell not surviving, POL-Q comes to the rescue by performing its two-step handiwork. First, it replaces the site of a missing or chemically changed base by inserting a new base—even if its choice from one of the four bases is not complementary to the base opposite. In a correct sequence strand, A always pairs with T and G always pairs with C, but POL-Q, the researchers report, seems to favor adding an A regardless of the missing base.
