Researchers measure the ’heat of life,’ offering clues to DNA damage

A Rutgers-led team has produced the first ever measurement of the “heat of life” – the energies involved in DNA replication and synthesis. The researchers’ findings have opened the door to a better understanding of the origins of replication errors that can result in genetic mutations and serious illness. This is crucial knowledge for the development of medical diagnostics and treatments of genetic disorders.

“Our measurements represent the first direct determination of the energies and their transformations in this most fundamental process in biological chemistry,” said principal investigator Kenneth J. Breslauer, Linus C. Pauling Professor, and dean and director of the Division of Life Sciences, Rutgers, The State University of New Jersey.

Breslauer explained that the measurements can be used to construct a virtual landscape that traces the precise energy differences between correct and incorrect DNA synthesis. The differential energy signatures signal the presence of DNA damage, potentially repairable by protein systems inside the cell or specifically designed drugs administered from the outside, or both.

“Knowing the nature and magnitude of the forces involved in correct and incorrect DNA synthesis is essential for rationally designing strategies for intervention, including new drug therapies,” said Breslauer. “This knowledge can position us to begin to intervene, enabling us to halt incorrect synthesis through the introduction of highly targeted external agents.

“The only reason we are not a bunch of mutants walking around is that we have exquisite repair systems that can recognize these damaged sites and repair them before they replicate. And, if they do escape initial repair and replicate, we have additional repair systems that find the damage that was replicated and delete it,” said Breslauer, noting the contributions of Rutgers’ recent National Medal of Science winner Evelyn Witkin to an understanding of these repair systems.

On rare occasions, both systems fail and when they do, a damaged piece of DNA can be carried on to the next generation. This might result in a particular protein not being able to be made in the offspring or even in the parent. Or, it might result in the improper regulation of a gene that controls cell growth, thereby precipitating uncontrolled growth and the formation of tumors.

DNA reproduces by acting as a template for copying itself, using ingredients available within the cell. Replication, the same as synthesis in this case, is required for any organism to develop, grow and pass on its genetic information. DNA damage is fairly common, a byproduct of our environment and normal metabolism.

In a paper appearing in the Proceedings of the National Academy of Sciences, Breslauer and his colleagues describe their use of a novel combination of technology and chemical biology. They employed the world’s most sensitive thermal detection system, accurate to a millionth of a calorie, to measure reaction heats in a uniquely formulated “DNA soup.”

“The degree to which this constitutes a breakthrough will be determined by how researchers here and elsewhere build upon it,” Breslauer continued. “It is a foundation that is a necessary, but not sufficient, step in the direction of being able to understand and to regulate DNA synthesis, not only in the lab, but in living organisms.”

The Human Genome Project and subsequent revelations provided by X-ray crystallography and nuclear magnetic resonance spectroscopy (NMR) have taught us a great deal about structure in biological systems. Breslauer points out, however, that there is still much to be learned about function and overall driving forces.

He makes the analogy of an automobile, in which knowing what all its component parts look like – the engine, the transmission, the brakes, etc. – still won’t allow you to fix the car if it is not running properly, unless you know the function of each part and the energy transfer between parts.

“These energy studies are essential to bridge the gap between structure and function, a bridge that is needed for our understanding of how biological processes operate and are controlled,” Breslauer said.