The grant to Lata Balakrishnan, an associate professor in the Department of Biology at the School of Science at IUPUI, will support research to understand how regulatory processes ensure the accuracy of a cell’s DNA when it is duplicated and how dysregulation of this process can lead to cancer. The dysregulation of DNA duplication is particularly common in pancreatic cancer and blood cancers, such as leukemia.
“Almost everyone knows someone who has been diagnosed with cancer,” Balakrishnan said. “Successful treatments make headlines since the impact on the patients is clear. However, to make these innovative therapeutic discoveries, we need to first understand specific biological processes within the cell and how dysregulation of these processes leads to development of disease such as cancer.”
An adult human’s body is made up of approximately 30 trillion cells, each carrying the same genetic message encoded in DNA, which is composed of 6 billion “letters.” During a cell’s division, the DNA code from the “mother cell” is duplicated, and one copy goes into each of two “daughter cells.” This process is called DNA replication.
“Each time the cell divides, it needs to accurately duplicate the genetic information,” Balakrishnan said. “Our genetic information is constantly under attack from external and cellular sources that change the DNA letters present in the genetic information.
“If these changes are not caught and corrected by a process known as DNA repair, then the incorrect letter is copied during the replication process. The proteins that are involved in the duplicating process are complex and need to work in perfect synchrony with each other for error-free replication. If there is an error in cancer-related genes, then it will lead to disease.”
Cells that divide more often are prone to accumulate more errors, leading to increased chances of cancers. Pancreatic cancer and blood cancers often have high rates of DNA replication errors. Balakrishnan and her team are studying how the proteins involved in duplicating the genetic information interact with the DNA and other proteins in the pathway.
“To better grasp this hugely complex process of DNA replication and repair within our cell, we need to study individual interactions between protein and DNA,” Balakrishnan said. “Understanding basic mechanisms in isolation gives us a better understanding of how a mutation either in the DNA or the protein can lead to the progression of diseases.”
As part of the research, Balakrishnan’s team will test a class of cancer drugs known as histone deacetylase inhibitors, or HDACIs, in order to understand their impact on the efficiency of DNA replication and repair. The goal is to understand the multiple factors that contribute to maintenance of the reliability of the replication process.
“Using a combination of novel proteomic and biochemical quantitative methodologies, we will characterize how replication efficiency is altered by cellular chemical modifications that influence the activities of the proteins involved in the replication process,” Balakrishnan said.
“Our studies will provide valuable insight into how maintenance of the genome is impacted by altering cellular acetylation levels,” she added. “This knowledge can be harnessed to develop precision medicine targets for patients that have developed resistance to cancer treatments and can also be used for improving targeted therapies for a subset of cancers.”
Balakrishnan will collaborate with researchers from the IU Melvin and Bren Simon Comprehensive Cancer Center and the IU School of Medicine’s Proteomics Core Facility.