Breakthrough Discovery: Scientists Unveil the ‘Just Right’ Zone for DNA Structure, Paving the Way for Revolutionary Drug Innovations

In a groundbreaking revelation that may alter our understanding of cellular fortitude and flexibility, researchers at Scripps Research have unveiled the intricate interactions between an ancient inorganic polymer of phosphate known as polyphosphate (polyP) and two fundamental components of life: DNA and the mineral magnesium. These elements concocted clusters of minuscule liquid droplets—termed condensates—with adaptable and versatile structures.

PolyP and magnesium participate in numerous biological functions. Therefore, the insights garnered could prompt novel approaches for modulating cellular reactions, which could lead to significant ramifications in translational medicine.

The resulting research, published in Nature Communications on October 26, 2024, unveils a delicate “Goldilocks” zone—a precise concentration range of magnesium—where DNA coils around polyP-magnesium ion condensates. Analogous to a fragile eggshell encasing a liquid-like core, this seemingly straightforward formation may assist cells in organizing and safeguarding their genetic material.

This endeavor commenced as a partnership between co-senior authors Associate Professor Lisa Racki, Ph.D., and Professor Ashok Deniz, Ph.D., both affiliated with the Department of Integrative Structural and Computational Biology at Scripps Research. Racki had been examining these structures within bacterial cells, while Deniz’s neighboring lab had been investigating the physical chemistry of biomolecular condensates for the past decade. They realized that collaboration was essential to unravel these primordial interactions.

“We were aware that DNA was situated close to the magnesium-rich polyP condensates within cells, but the stunning spheres of DNA that illuminated under the microscope completely took us by surprise,” Racki states.

“As molecular detectives, witnessing these structures sparked intriguing inquiries for us regarding the physics and mathematics of the DNA shells and their potential influence on the polyP condensates,” Deniz adds.

Their microscopy visuals disclosed that DNA coiled around a condensate, producing a thin barrier akin to an eggshell. This shell could alter molecule transport and also impede fusion: the phenomenon where two condensates merge into one. In the absence of DNA shells, polyP-magnesium ion condensates merged readily—much like how oil droplets and vinegar combine in a salad dressing jar when agitated.

Nonetheless, meticulous observation illustrated that fusion overall slowed down to varying degrees, contingent on DNA length. The researchers conjectured that longer DNA led to increased entanglement on the surfaces of condensates—analogous to how long hair becomes more tangled than shorter hair.

DNA is over 1,000 times thinner in diameter compared to condensates, making the molecular details challenging to capture visually. Fortunately, two other faculty members at Scripps Research, Assistant Professor Danielle Grotjahn, Ph.D., and Scripps Fellow Donghyun Raphael Park, Ph.D., developed the infrastructure necessary for such imaging.

Collaborating with Park and with assistance from Grotjahn, the researchers utilized cryo-electron tomography to meticulously observe the surfaces of the condensates. Employing electrons instead of light, this method captures three-dimensional, high-resolution images of samples that have been quickly frozen to maintain their structures. The new visuals unveiled that DNA forms filaments extant from condensate surfaces, reminiscent of tangled hairs.

Another essential revelation: DNA shell formation transpired only within a particular magnesium ion concentration range—excessive or insufficient amounts, and the shell failed to form. This “Goldilocks” principle emphasizes how cells can modulate condensate structure, dimension, and functionality merely by adjusting controllable parameters.

“Even though we perceive cellular interfaces as boundaries, they simultaneously create a fresh landscape by providing a surface for molecules to arrange themselves,” observes Racki. “DNA may not truly be an entangled chaos at the surface but is instead systematically structured by these condensates.”

In this regard, Deniz and Racki are particularly keen on comprehending DNA supercoiling—how DNA twists like a spring to fit within cells.

“Cells must manage their DNA spirals,” clarifies Racki. “Interestingly, the mathematics governing DNA supercoiling results in ‘action-at-a-distance’ effects—similar to how twisting a rope can induce coils far from your grip.”

The researchers hypothesize that DNA interactions with polyP condensates in cells could transmit local modifications in DNA supercoiling across considerable distances, leading to wider shifts in gene expression and cellular function. Exploring this phenomenon is among the next objectives for the team.

“We’re thrilled about the potential of utilizing these insights to create new instruments for cellular regulation—possibly simpler, more economical strategies to handle biomatter in biomedicine,” expresses Deniz.

Alongside Deniz, Racki, Grotjahn, and Park, authors of the study, “Reentrant DNA shells tune polyphosphate condensate size,” include co-first authors Ravi Chawla and Jenna K. A. Tom, along with Tumara Boyd, Nicholas H. Tu, and Tanxi Bai from Scripps Research.