Navigation Links
Preventing cells from getting the kinks out of DNA

Many standard antibiotics and anti-cancer drugs block the enzymes that snip the kinks and knots out of DNA DNA tangles are lethal to cells but the drugs are increasingly encountering resistant bacteria and tumors.

A new discovery by University of California, Berkeley, biochemists could pave the way for new research into how to re-design these drugs to make them more effective poisons for cancer cells and harmful bacteria.

"The development of the anti-bacterial and anti-tumor agents that target these enzymes thus far has been done entirely in the absence of any visualization of how these drugs actually interact with the protein itself. And they have done remarkably well," said James Berger, UC Berkeley professor of molecular and cell biology. "But we have increasing problems of resistance to these drugs. Being able to see how these drugs can interact with the enzyme and DNA is going to be critical to developing the next generation of therapeutics that can be used to overcome these resistance problems."

Berger and colleagues at Emerald BioStructues of Bainbridge Island, Wash., and Vanderbilt University in Nashville, Tenn., report their new findings in a paper to be printed in the journal Nature and made available last week as an advance online publication at

The tangles in DNA, like those in a string of holiday lights, are a result of packing some six feet of DNA into a cell nucleus so small that it is invisible to the naked eye. Every time a cell divides, it has to unpack, duplicate and repack its DNA, generating about a million tangles among the newly-copied chromosomes in the process.

As Berger has shown in previous work, enzymes called topoisomerases home in on the sharp turns in a knot and then progressively snip the DNA, unloop it, and restitch it flawlessly. If, however, the enzyme slips up, that one snip can turn into a potentially mutagenic or cell-killing DNA break.

While the protein structure of these topoisomerases is known, the details of the chemical reactions that take place between the enzyme and DNA, and their reaction with the drugs that bind both, remain a mystery, Berger said. In fact, one of the main puzzles is why antibiotics like ciprofloxacin (Cipro) and anti-cancer drugs like etoposide, which vary widely in structure, have the same effect: jamming the enzyme and causing a break in the double-stranded DNA helix.

Berger and his colleagues found a way to obtain a picture that shows the interaction of the protein bound to DNA. The next step is to do the same for a drug bound to the protein/DNA complex, getting an image of exactly how these drugs interfere with the knot elimination machinery.

"The technique we used to trap this complex so that we could actually crystallize it and image it we think now gives us a handle on how to go after drug-bound complexes of human topoisomerases that have long eluded the field," said Berger, who also is a staff scientist at Lawrence Berkeley National Laboratory (LBNL).

The scientists' new picture of the enzyme bound to DNA also turned up something totally unexpected. Most enzymes that bind DNA to snip or stitch it together use two metal ions typically two magnesium ions to catalyze the reaction. Berger found that type II topoisomerases, which target double-stranded DNA, make use of only one of their two magnesium ions and instead use the amino acid arginine as their second catalytic center. The second magnesium merely provides structural integrity to the protein.

"We stumbled upon a new kind of cleavage mechanism for DNA, an example of a protein that uses a completely new approach for the same mechanism," Berger said. "It speaks to the evolutionary plasticity and adaptability of nature that continuously amazes us with finding new ways to carry out reactions that it needs to perform."

Berger now plans to use his trick to trap the enzyme on a short segment of DNA, allowing him to collect enough to crystallize and analyze in an X-ray beam from LBNL's Advanced Light Source, to trap both drug and enzyme on DNA. Once crystallized and imaged, he will have the first full picture of a topoisomerase interacting the way it does in a real cancer cell or microbe.


Contact: Robert Sanders
University of California - Berkeley

Related biology news :

1. Vaccines preventing pneumococcal disease protect African children with sickle-cell disease
2. Preventing gastric cancer with antibiotics
3. Preventing or reversing inflammation after heart attack, stroke may require 2-pronged approach
4. New finding in cell migration may be key to preventing clots, cancer spread
5. UC Davis research confirms benefits of calcium and vitamin D in preventing fractures
6. New study suggests minke whales are not preventing recovery of larger whales
7. Mango effective in preventing, stopping certain colon, breast cancer cells
8. Preventing allergies
9. Climate change poker: The barriers which are preventing a global agreement
10. NIH funds work at WPI on regenerating heart tissue and preventing urinary tract infections
11. Preventing ear infections in the future: Delivering vaccine through the skin
Post Your Comments:
(Date:10/29/2015)... Oct. 29, 2015  Rubicon Genomics, Inc., today ... distribution of its DNA library preparation products, including ... new ThruPLEX Plasma-seq kit. ThruPLEX Plasma-seq has been ... of NGS libraries for liquid biopsies--the analysis of ... prognostic applications in cancer and other conditions. Eurofins ...
(Date:10/27/2015)... YORK , Oct. 27, 2015 In ... major issues of concern for various industry verticals such ... is due to the growing demand for secure & ... in various ,sectors, such as hacking of bank accounts, ... for electronic equipment such as PC,s, laptops, and smartphones ...
(Date:10/26/2015)... and LAS VEGAS , Oct. 26, ... , an innovator in modern authentication and a founding ... the launch of its latest version of the Nok ... organizations to use standards-based authentication that supports existing and ... Authentication Suite is ideal for organizations deploying customer-facing applications ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... Israel , Nov. 24, 2015  Tikcro Technologies Ltd. (OTCQB: TIKRF) ... on December 29, 2015 at 11:00 a.m. Israel ... Electra Tower, 98 Yigal Allon Street, 36 th Floor, ... of Eric Paneth and Izhak Tamir to the ... Rami Skaliter as external directors; , approval of an amendment to ...
(Date:11/24/2015)...  Twist Bioscience, a company focused on synthetic ... Bioscience chief executive officer, will present at the ... 2015 at 3:10 p.m. Eastern Time at The Lotte New ... --> --> About Twist ... on Twitter. Sign up to follow our Twitter ...
(Date:11/24/2015)... ... 24, 2015 , ... InSphero AG, the leading supplier of easy-to-use solutions for ... Aregger to serve as Chief Operating Officer. , Having joined InSphero in ... and was promoted to Head of InSphero Diagnostics in 2014. There she ...
(Date:11/24/2015)... - ProMetic Life Sciences Inc. (TSX: PLI) (OTCQX: PFSCF) ("ProMetic" ... , President and Chief Executive Officer of ProMetic, will be ... th Annual Healthcare Conference to be held at the ... st , at 8.50am (ET) and ProMetic,s management team ... presentation will be available live via a webcast accessible at ...
Breaking Biology Technology: