Addition of some extra to our knowledge about DNA Repair after a long time

A Florida State University College of Medicine researcher has made a breakthrough that changes our knowledge of the body's DNA repair process and could lead to novel cancer and other disease chemotherapeutic therapies.

One of the great mysteries of medical research is how DNA can be repaired after it has been broken, but the pathways involved in the repair process alter at different phases of the cell life cycle. The damaged material is removed in one of the repair routes known as base excision repair (BER), and a collection of proteins and enzymes work together to synthesize DNA to fill in and then seal the gaps.

FSU researchers, led by Eminent Professor Zucai Suo, revealed that BER has a built-in mechanism to boost its efficiency; it just needs to be caught at a very specific stage in the cell life cycle.

Polymerase beta (PolyB) is a BER enzyme that performs two functions: it produces DNA and initiates a reaction to clear up the residual "chemical garbage." Suo's team discovered that collecting PolyB when it is naturally cross-linked with DNA allows the enzyme to build new genetic material 17 times faster than when the two are not cross-linked after five years of research. This shows that during BER, the two roles of PolyB are intertwined rather than autonomous.

The study contributes to a better knowledge of cellular genomic stability, therapeutic efficacy, and chemotherapy resistance.

"Cancer cells proliferate at a tremendous rate, and their DNA is subjected to a great deal of damage," Suo explained. "When a doctor employs particular medications to assault the DNA of cancer cells, the cancer cells are subjected to more DNA damage." Cancer cells will perish if they are unable to repair DNA damage quickly. Otherwise, the cancer cells will survive and develop drug resistance.

The research is published in the Proceedings of the National Academy of Sciences this month.

Unlike prior studies that imitated the process, this study looked at naturally cross-linked PolyB and DNA. Researchers had discovered the enzymes involved in BER before this study, but they didn't fully grasp how they interacted.

"When we have nicks in DNA, horrible things can happen," said Thomas Spratt, a professor of biochemistry and molecular biology at Penn State University College of Medicine who was not involved in the study. "What Zucai discovered teaches us something we didn't know before, and he employed a variety of ways to get at his conclusions."

The researchers created a redesigned BER pathway and is testing it in human cells, in addition to exposing PolyB's functional dynamics.

"We were able to go deeper into a key pathway for which Tomas Lindahl, the pioneer, shared the Nobel Prize in Chemistry in 2015," Suo added.

Reference:

Adarsh Kumar, Andrew J. Reed, Walter J. Zahurancik, Sasha M. Daskalova, Sidney M. Hecht, Zucai Suo. Interlocking activities of DNA polymerase β in the base excision repair pathway. Proceedings of the National Academy of Sciences, 2022; 119 (10) DOI: 10.1073/pnas.2118940119