News Section | Cell Biology
Enzyme crucial to DNA replication may be potent anti-cancer drug target
Scientists have found that an enzyme essential for DNA replication and repair in humans works in a way that might be exploited as an anti-cancer therapy.
Researchers at The Scripps Research Institute and Lawrence Berkeley National Laboratory focused on a member of a group of enzymes called flap endonucleases, which are essential to the life of a cell.
The findings showed new, clearly defined crystal structures of the enzyme FEN1 in action—demonstrating it functions in a way opposite to accepted dogma.
“The research produced very accurate structures showing DNA before and after being cut by FEN1 activity, providing a basis for understanding a whole superfamily of enzymes that must cut specific DNA structures in order for DNA to be replicated and repaired,” said team leader John Tainer.
This superfamily includes important targets for the development of new cancer interventions, Tainer added.
Many cancers show high levels of FEN1 expression, which in some cases is correlated to tumor aggression. For these cases, FEN1-specific inhibitors may have chemotherapeutic potential.
To determine what FEN1 looked like in action, co-author Andy Arvai led the difficult but ultimately successful effort to grow crystals of the human FEN1 protein bound to DNA.
The end result was a highly detailed and accurate model showing the structures of DNA before and after being cut by FEN1.
Researchers know that mutations in FEN1 can predispose humans to cancer growth because errors in flap removal can create unstable DNA that promotes cell growth and division.
And studies in mice have shown that when one of two inherited FEN1 genes are knocked out, the mice are predisposed to cancer development if their DNA is damaged.
The study has been published in the April 15, 2011 issue of the journal Cell.
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