Scientists at Weill Cornell Medicine and the National Heart, Lung, and Blood Institute, a division of the National Institutes of Health, have made a groundbreaking discovery that showcases the ability of DNA to mimic the functions of proteins through intricate three-dimensional folding.
Their research, recently published in the journal Nature, employed advanced imaging technologies to reveal the unique and multifaceted structure of a synthetic DNA molecule. This engineered molecule was designed to emulate the behavior of a protein called green fluorescent protein (GFP), originally found in jellyfish and widely used as a luminescent marker in scientific laboratories.
The findings represent a significant advancement in our understanding of DNA’s capacity to fold into complex shapes. This knowledge will aid researchers in constructing DNA molecules with diverse configurations for various laboratory and clinical applications. For instance, the creation of an all-DNA fluorescent tag that imitates GFP would be highly beneficial in labeling specific segments of DNA in biological studies and diagnostic test kits, all while being cost-effective.
Dr. Samie Jaffrey, a co-author of the study and the Greenberg-Starr Professor of Pharmacology at Weill Cornell Medicine, expressed the transformative nature of these findings, stating, “These discoveries truly redefine the possibilities of what DNA can achieve.”
In its natural state, DNA primarily exists as a double-stranded helix, serving as a stable repository of genetic information. However, most complex biological processes within cells are carried out by other molecules, particularly proteins.
In a previous study, Dr. Jaffrey and his team uncovered a single-stranded DNA molecule that folds in a manner resembling the activity of GFP. This DNA, referred to as “lettuce” due to its fluorescent emissions, binds to a small organic molecule known as a fluorophore, similar to the one found in GFP. By exerting pressure on the fluorophore, lettuce activates its ability to fluoresce. The researchers successfully demonstrated the use of the lettuce-fluorophore combination as a fluorescent tag for the rapid detection of SARS-CoV-2, the virus responsible for COVID-19.
Although Dr. Jaffrey and his team identified lettuce by screening numerous single-stranded DNAs, they were uncertain of the structural basis behind lettuce’s activating ability. To determine this structure, they collaborated with Dr. Adrian R. Ferré-D’Amaré, a senior investigator at the NHLBI.
Under the leadership of Dr. Luiz Passalacqua, a research fellow in Dr. Ferré-D’Amaré’s team, advanced imaging techniques such as cryo-electron microscopy were employed to elucidate the atomic-scale structure of lettuce. The researchers discovered that lettuce folds into a configuration featuring a previously unseen four-way junction of DNA at its core, enclosing the fluorophore in a manner that activates its fluorescence.
Furthermore, the researchers observed that lettuce’s folding is stabilized by bonds between nucleobases, the fundamental building blocks of DNA often referred to as the “letters” in the DNA alphabet.
Dr. Ferré-D’Amaré emphasized, “What we have uncovered is not DNA imitating a protein, but rather DNA mimicking GFP in its own unique way.”
These findings are expected to accelerate the development of fluorescent DNA molecules, including lettuce, for applications such as rapid diagnostic tests and various scientific endeavors where a DNA-based fluorescent tag is desirable.
Dr. Jaffrey emphasized the significance of studies like this in the creation of new DNA-based tools, stating, “Research of this nature is indispensable for the advancement of DNA-based technologies.”
References:
- “Intricate 3D architecture of a DNA mimic of GFP” by Luiz F. M. Passalacqua, Michael T. Banco, Jared D. Moon, Xing
