Study may impact treatment of cancer, other diseases

Kishor Bhakat, Ph.D., an associate professor in the UNMC Department of Genetics, Cell Biology and Anatomy, took part in a recently published study that could have an impact on developing novel therapeutic drugs for various diseases as DNA damage is the hallmark of cancer, diabetes, neurodegenerative diseases.

The study was published in the May issue of the prestigious journal “Proceedings of the National Academy of Sciences, USA.” PNAS is a multidisciplinary journal that publishes novel work that has a broad impact or implication in sciences.

Dr. Bhakat worked with former student and first author Shrabasti Roychoudhury, Ph.D., and others on the study, which draws on his 20 years of work with APE1 — a common, yet critical enzyme found in human cells – and its connection to another unusual tetrahelical DNA structure, G-quadruplex or G4.

APE1 shows up when there is endogenous oxidative damage to DNA and begins a repair process.

It’s a pretty nifty enzyme, Dr. Bhakat said, working to repair damage to DNA caused by many diseases.

After honing in on APE1 in the genome of multiple types of cancer cells, Dr. Bhakat and his research team discovered that the oxidative damage APE1 was attempting to repair wasn’t just spread randomly throughout the cell. It was localized to a particular region of the genome.

But more surprisingly, the team also discovered that everywhere APE1 showed up to begin repairs, G4 also was present. (It is not yet clearly known how G4 structures form in the genome in cells.)

The correlation got Dr. Bhakat wondering: Why was it there?

His findings of how oxidized DNA bases and APE1 regulates the formation of G4 structures in the genome are a major part of the newly published study. The discovery of the direct link between APE1 and G4 will allow further research that may lead to therapeutic breakthroughs.

“Oxidative base damage in cells is conventionally viewed as detrimental for cellular processes, as it can induce mutation or may block transcription and replication,” Dr. Bhakat said. “Our study provides evidence that oxidized guanine residues in G4 sequences, followed by binding of APE1, is essential for the formation of G4 structures that regulate many biological processes.”

In short, DNA damage may not always be bad for the cells. Rather, targeted damage in specific context is essential to regulate DNA secondary structure and controlling gene expression and replication.

Dr. Bhakat called this concept “paradigm-shifting.”

“This study by Dr. Bhakat and his team is highly significant, as it opens a new area of research linking gene transcription with DNA repair pathways in normal physiology,” said Vimla Band, Ph.D., chair of genetics, cell biology and anatomy at UNMC and a co-author on the paper.

“It also opens potential avenues to target G4-dependent expression of cancer-causing genes with APE1 inhibitors” she said. “This would intervene in the growth of cancer and its metastatic spread to other organs, a dominant source of cancer-associated deaths.”

As for Dr. Bhakat, he is going to continue to look into this complex APE1-G4 structure and the role it plays in regulating or causing tumor growth.

“This is only the beginning,” he said. “The possibilities are quite exciting.”