Study suggests that enzyme crucial to provide potent anti-cancer drug target for DNA replication

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Works an enzyme for DNA replication and repair people in a way that could be exploited as anti-cancer treatment, say researchers at the Scripps Research Institute and Lawrence Berkeley National Laboratory.

The research, the 15 April 2011 issue of the journal cell, focused on a member of a group of enzymes called flap endonucleases, that are the life of a cell of essential. The results show new, clearly-defined crystal structure of the enzyme minute in action to demonstrate that it acts in a manner to accepted dogma.

"This work represents a ground-breaking progress in the understanding of the minute," said Team Manager John Tainer, Professor and member of the Skaggs Institute for chemical biology at the Scripps Research and senior scientist at the Lawrence Berkeley National Lab. "the research produced very accurate structures show DNA before and after by minute fn Aktivitätdie a basis for understanding a whole superfamily of enzymes which specific DNA must cut so that DNA replicates and repairs are structured."

This superfamily important objectives for the development of new cancer interventions containing added Tainer. High minute expression that aggression is correlated in some cases with tumor show many types of cancer. In these cases, minute specific inhibitors can have chemotherapeutic potential.

Co-author remarked "A better understanding of the minute structure and function can have long-term positive benefits for human health" Andy Arvai, a research associate at the Scripps Research.

Working quickly with exquisite precision

It has its double helix to replicate DNA, relax the coiled together is made of two strands of amino acids. This can be unloaded done by the two strands are separated by a replication fork. These strands that form two branches from the replication fork tines, serves as a beach complementary template for the production of a new.

This task is known as the "leading" the two tracks is quite simple. The replication fork moves along by so-called 3' (three Prime) end to 5' (five Prime) and DNA polymerase synthesizes a 5' to 3' complementary beach.

But because the two strands are anti-parallel, which means that they are aligned in opposite directions, the work of the DNA polymerase, which only in the 5' to 3' direction to work, is more difficult on the so-called lagging strand. This line needs to be replicated into pieces, which are known as Okazaki fragments, in the vicinity of the replication fork. These fragments contain a "primer," a strand of RNA, which serves as a starting point for DNA synthesis.

Here comes minute fn Tainer said that RNA primer on the 5' flap, which every 100 base pairs or so on the lagging strand is taking place, removed. It is a huge task that will be done fast and deliver to glue the ends of replicated DNA on the lagging strand together to an intact chromosome has. "A DNA double helix in a cell to replicate, you have a 5' flap cut off so that you do not have a base pair to many or a base pair too few and you primers in each cell cycle must make exactly with 50 million Okazaki" Tainer said. "It was always a mystery as minute as efficiently and as fast can cut exactly these valves." "It is an amazing, efficient molecular machine for precise cut DNA."

Arvai was difficult to determine what looked like minute in action, but ultimately successful attempt of human minute crystals grow protein to DNA bound. The Crystal structure analysis team then used to determine the atomic structure of the complex. The scientists solved with Lawrence Berkeley National Laboratory's advanced light source Beamline, called the PROPHETINNEN, three different crystal structures.

The end result was a very detailed and accurate model the structures of DNA shows before and after by the minute.

Former crystal structures proposed, that minute first grabs on the door of the 5' individual DNA, films on the common stranded where duplicated DNA, and cuts and patches is the primer. But she mixed new study found that in fact binds a minute, turn, and then cuts the DNA.

"It duplex DNA binds, it bends right in a single-stranded DNA at the door, tilts from two base pairs and cut between them," said Tainer. "This gives you very precise control minute a sophistication that we had not expected."

Notes on the cancer control

Scientists know that mutations in minute can prepare people to cancer growth as error in flap to create distance unstable DNA that promotes cell growth and cell division. And studies in mice have shown that if one of the two are inherited minute fn gene knocked out, the mice to cancer development are invested when their DNA is damaged.

While other DNA repair mechanisms will help to compensate for minute error or missing minute fn "you a lot of minute need after activity, DNA repair and replication to work properly', Tainer said.

This indicates that in tumours already lacks a set of repair proteins, selectively inhibits the function of minute cells can replicate quickly as an effective cancer treatment. "The Achilles heel of cancer cells defective DNA repair pathways," said Tainer, "because, makes them more susceptible to traditional therapies, such as chemotherapy and radiation." "If to these therapies to tumors do not damage cancer repair can, they will die."

This is the paradox of the DNA repair: while a defect in the DNA repair can cause cancer, can tap a number of backup systems tumors make vulnerable to cancer therapies.

"I hope that our observation of the operation could mechanistically a basis for a future cancer drug, minute", Tainer said. "We must offer as possible shall be deleted, as many lifelines in cancer cells to an effective treatment."

The study was supported by grants from the national institutes of health and the biotechnology and biological of Sciences in the United Kingdom Research Council (BBSRC).

Sources: at the Scripps Research Institute, AlphaGalileo Foundation.