Researchers at The University of Kansas Cancer Center are working to fill the knowledge gap between DNA damage and cancer, including developing approaches to manipulate the DNA damage response to treat and prevent disease. Their research on an integral DNA repair protein was recently highlighted in the scientific journal, Nature Communications.
Carcinogens, in the form of environmental hazards such as UV radiation and tobacco smoke, can cause mutations and/or breaks in our DNA (which is comprised of genes). When left unrepaired, these altered genes are a primary cause of cancer.
A DNA repair enzyme, termed APE1, removes DNA damage and mismatched base pairs by cutting them out of the genome during DNA repair.
"APE1 is one of the most important enzymes in DNA repair. But prior to our study, the process of how DNA is damaged and then repaired by APE1 was not well understood," says assistant professor Bret Freudenthal, PhD, member of KU Cancer Center's Cancer Biology program and KU Medical Center's department of Biochemistry and Molecular Biology. Freudenthal is also affiliated with the department of Cancer Biology.
With unique approaches and the help of sophisticated instrumentation, including an in-house X-ray diffractometer – one of only a few such machines in the region – Freudenthal and his lab members are able to look at DNA repair processes at the atomic level. This approach can decipher the precise arrangement of atoms within a molecule, and it allows researchers to see how DNA and key repair proteins interact during DNA repair and replication. This groundbreaking work is the first to illustrate how the APE1 enzyme cleans up mismatched and damaged DNA ends, also known as "dirty ends," that block successful repair.
Amy Whitaker, PhD, a member of Freudenthal's lab and lead author of the study, notes that halting the repair of DNA damage has been shown to make current cancer treatments more effective.
"Ultimately, we hope the findings from this study are translated into guides for rational drug design where they can directly aid in the development of more effective chemotherapeutics and synergistic drug combinations that target DNA damage and repair," Whitaker says.