First look at an enzyme target for cancer treatment

Friday, 21 December, 2007

US scientists have modelled an enzyme critical to the process of DNA transcription and replication which could be a prime target for antibacterial and anticancer drugs.

Researchers with the US Department of Energy's Lawrence Berkeley National Laboratory and the University of California have produced the first three-dimensional structural images of a DNA-bound Type II topoisomerase (topo II), responsible for untangling coiled strands of the chromosome during cell division.

Preventing topo II from disentangling a cell's DNA is fatal to the cell, which makes inhibiting the enzyme a possible method of fighting bacterial infections and some forms of cancer.

The structural image of topo II should help in the development of future antibacterial and anticancer drugs that are even more effective and carry fewer potential side effects than current medicines.

"Topo II has been called 'nature's magician' because it literally can move one DNA segment through another," said James Berger, a biochemist and structural biologist who led the research.

"The enzyme cleaves a double-stranded DNA, passes a second duplex through the break and then immediately repairs the broken strands. This enables topo II to control the topology of DNA for chromosome segregation and disentanglement."

Using exceptionally intense beams of X-rays from an advanced light source (ALS), the researchers obtained high-resolution, 3D crystallography images of the DNA binding and cleavage core of the enzyme taken from yeast as it interacted with a segment of DNA.

The images revealed that topo II causes a sharp bend — 150µ or more — in the DNA segment at the cleaving point. The folding of the DNA segment helps topo II to recognise where it should disentangle DNA strands.

"In many ways, the enzyme works like a set of canal locks, opening and closing certain protein interfaces, or gates, to control the passage of one DNA segment through another without accidentally letting go of the DNA and breaking the chromosome irreversibly," Berger said. "Our structural studies should serve as a useful platform for future efforts to understand the chemical basis of DNA cleavage, and for efforts to understand and improve anti-topoisomerase therapeutics."

Antibacterial and anticancer drugs that target topo IIs and other topoisomerases, such as the quinolone family of antibiotics (including the commonly-used ciprofloxacin), work by preventing the enzymes from completing their tasks. When the drug affects topo II, the cleaved segments of DNA remain attached to the enzyme instead of resealing. The number of damaged DNA strands mount until the cell dies.

Since the targeting of these drugs has not been optimal, there have been side effects that include secondary cancers, antibiotic toxicity and microbial resistance.

"In some respects, it's amazing that the anti-topo II drugs have been so effective," said Berger.

"To the credit of the biochemists and chemists, their discovery and refinement of these compounds have already made a remarkable therapeutic impact. Yet, to the best of my knowledge, all of the work on these drugs has been done without a good picture of how type II topoisomerases engage DNA.

"Our new structural knowledge fills that hole, and should be of significant help for overcoming resistance and for guiding the development of future anti-topo II drugs with improved efficacy."

Berger and his research group are now looking into producing crystallographic images of topo II as it interacts with antibacterial and anticancer drugs to determine what the rules for engagement are.

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