Crammed inside every human cell are numerous strands of chromosomal DNA that, if laid end-to-end, would span a distance of about two meters. A special enzyme mechanically untangles the DNA, keeping our chromosomes from resembling a string of Christmas tree lights jammed into a box after the holiday. Someday, biochemist James Berger's efforts to understand the same enzyme in cancer cells could lead to new tumor-fighting drugs.
The enzyme is called a topoisomerase, so-named because it literally resolves topological dilemmas like knots and twists. Essential to the survival of many cells and viruses, topoisomerases have in recent years become prime targets for anticancer and antimicrobial drugs. Indeed, many traditional forms of chemotherapies are based on natural and synthetic compounds that inhibit the process. But Berger hopes his efforts to unveil the enzyme's subtle mechanics may inform the development of better drugs that throw a wrench in the cancer's topoisomerases while sparing healthy cells.
Think of a topoisomerase as a tiny multi-armed robot that clamps around a knot or twist in the DNA. One set of the arms grabs either side of the knot and pulls the strand apart while another uses a free segment of DNA to push through the break. After the strand is closed again, the DNA that was just transported through the break is expelled from the bottom of the enzyme.
"All of the components are coupled and coordinated so that the enzyme can remove two to three knots every second," Berger explains. "If it screws up though and doesn't paste the DNA back together correctly, the cell won't survive. That's the Achilles' Heel that many chemotherapeutics exploit."
Read the complete article by David Pescovitz at ScienceMatters