Hedglin Group Makes Strides in Cancer Research
The Hedglin group—led by Dr. Mark Hedglin, Assistant Professor of Chemistry and Biochemistry and Molecular Biology at Penn State—is tackling some of the critical questions facing cancer researchers. The group took on one such question in their first paper, “Replication protein A dynamically regulates monoubiquitination of proliferating cell nuclear antigen," which appeared in The Journal of Biological Chemistry.
The paper, which was authored in collaboration with the Benkovic group, addresses a long-standing obstacle faced by scientists studying cancer. Their work offers researchers an insight into one aspect of the disease that has been traditionally difficult to study.
Dr. Hedglin explains that humans have evolved elaborate pathways to "tolerate" damage to their DNA genome; this damage happens constantly and can be caused by environmental mutagens such as ultraviolet (UV) radiation from the sun and natural metabolites produced by our own cells. These pathways rely on a specific modification to a key accessory factor: the attachment of a small protein (ubiquitin) to PCNA, a critical accessory factor that encircles DNA and is utilized throughout DNA replication. This modification is referred to as PCNA monoubiquitination.
“PCNA monoubiquitination is highly specific,” Dr. Hedglin notes, “it only occurs on PCNAs that encircle sites of DNA damage...If PCNA monoubiquitination occurs at the wrong place at the wrong time, it can increase mutation frequency in DNA, which can ultimately lead to cancer.” He explains that scientists have struggled to study this phenomenon because of a lack of efficient techniques to detect and quantify this modification.
The team addressed this problem by developing a powerful fluorescent assay that allows PCNA monoubiquitination to be quantitatively monitored under conditions that mimic cellular environments. Through extensive studies using the assay, the researchers were able to determine that another key accessory factor, RPA, inhibits modification of PCNA on undamaged DNA and promotes modification of PCNA that is on damaged DNA.
The discovery is an important breakthrough in the field of cancer research, and it will play a vital role in scientists’ efforts to understand and treat cancer. “This dynamic regulation by RPA is unprecedented and has profound implications for the tolerance of DNA damage during DNA replication,” Dr. Hedglin explains.
Going forward, the groups plan to continue their work by using their fluorescent assay to explore how other key accessory factors regulate PCNA monoubiquitination when the human DNA genome is damaged. The work of the Hedglin and Benkovic groups also provides a powerful tool to other researchers studying this topic.