First Step to Untangle DNA: Supercoiled DNA Captures Gyrase Like a Lasso Ropes Cattle
Published:06 Jun.2024    Source:Baylor College of Medicine
A study published in the journal Science, researchers at Baylor College of Medicine, Université de Strasbourg, Université Paris Cité and collaborating institutions reveal how DNA gyrase resolves DNA entanglements. The findings not only provide novel insights into this fundamental biological mechanism but also have potential practical applications. Some DNA supercoiling is essential to make DNA accessible to allow the cell to read and make copies of the genetic information, but either too little or too much supercoiling is detrimental. For example, the act of copying and reading DNA overwinds it ahead of the enzymes that read and copy the genetic code, interrupting the process. It's long been known that DNA gyrase plays a role in untangling the overwinding, but the details were not clear.
"We typically picture DNA as the straight double helix structure, but inside cells, DNA exists in supercoiled loops. Understanding the molecular interactions between the supercoils and the enzymes that participate in DNA functions has been technically challenging, so we typically use linear DNA molecules instead of coiled DNA to study the interactions," said study researchers. "One goal of our laboratory has been to study these interactions using a DNA structure that more closely mimics the actual supercoiled and looped DNA form present in living cells." After years of work, the Zechiedrich lab has created small loops of supercoiled DNA. In the current study, their hypothesis was proven correct. As the DNA supercoils inside the nucleus, it twists and folds in different forms. This is the first step of the mechanism that prompts the enzyme for resolving DNA entanglements. Imagine watching the rodeo. Like roping cattle with a lasso, supercoiled looped DNA captures gyrase in the first step. Gyrase then cuts one double-helix of the DNA lasso and passes the other helix through the break to get free.
Researchers confirmed the observation of the path of the DNA wrapped in the loop around gyrase using magnetic tweezers, a biophysical technique that allows to measure the deformation and fluctuations in the length of a single molecule of DNA. Interestingly, the "DNA strand inversion model" for gyrase activity was proposed in 1979 by Drs. Patrick O. Brown and the late Nicholas R. Cozzarelli, also in a Science paper, well before researchers had access to supercoiled minicircles or the 3-D molecular structure of the enzyme. This work opens a myriad of perspectives to study the mechanism of this conserved class of enzymes, which are of great clinical value and supports new ideas on how DNA activities are regulated.