NEW YORK (Reuters Health) - New findings from studies using brewers yeast answer long-standing questions about how DNA polymerase-alpha, a protein responsible for initiating DNA replication, finds its place on the chromosome where replication begins.
“Minichromosome maintenance protein 10" (Mcm10) guides DNA polymerase-alpha to the replication site, Dr. Anja-Katrin Bielinsky and Robin Ricke of the University of Minnesota, Minneapolis, report in the October 22nd issue of Molecular Cell.
Mcm10 also maintains the stability of DNA polymerase-alpha, which Dr. Bielinsky called “a big surprise,” and the most important finding, in an interview with Reuters Health.
Polymerase-alpha is the only DNA polymerase capable of initiating DNA replication de novo. If Mcm10 is removed from cells, the team found, DNA polymerase-alpha’s catalytic subunit degrades, making the enzyme nonfunctional.
“The catalytic subunit is the heart of the DNA polymerase-alpha complex -- it’s a fairly big protein and it’s likely that’s why it needs some sort of stabilization,” Dr. Bielinsky said. “We think that Mcm10 is attached to it at all times and makes sure that it’s not being degraded.”
Mcm10 also has other interactions important to DNA replication, the researcher noted. “It’s a little bit like a coordinator -- it interacts with a lot of different things.”
Specifically, Mcm10 interacts with Mcm2-7, the helicase that is believed to unwind the DNA molecule so replication can occur. According to the researchers, Mcm10 physically links Mcm2-7 and DNA polymerase-alpha at the replication fork, allowing polymerization to follow unwinding. Mcm10 also binds directly to the DNA strand undergoing replication.
Mcm10’s multifunctionality makes an excellent target for cancer treatment, Dr. Bielinsky said. Blocking Mcm10 would not only inhibit its interaction with DNA polymerase-alpha -- it would also induce degradation of the larger molecule, she noted.
“Once we know which part of Mcm10 interacts with DNA polymerase-alpha, we will try to make small peptides to compete with this binding and disrupt it,” she said.
Another protein, Cdc45, had generally been considered to be the chaperone that guided DNA polymerase-alpha to the replication site, Dr. Bielinsky noted. Instead, it appears that Cdc45 activates the helicase of the Mcm2-7 complex.
Dr. Bielinsky said she expects Mcm10 to work similarly in human cells. “The functional domains of Mcm10 are evolutionarily conserved and so is the structure and function of DNA polymerase-alpha. We are now starting to experimentally address this question by analyzing Mcm10 in chicken B-cells.”
Source: Molecular Cell 2004;16:173-185. [ Google search on this article ]
MeSH Headings:Drugs, InvestigationalCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
