By Michele W. Sequeira

Molecular Shape Shifters

UNM Team Finds That Proteins Can Go From Reading DNA to Repairing it, Pointing the Way Toward New Cancer Treatments

Residing inside each of our cells, our DNA acts like a book of recipes for making proteins. But if a recipe is wrong, what does a cell do?

Peng Mao, PhD, and his team discovered an intricate series of events that cells use to repair our DNA as the recipes are being read. The team published their study in the July 20 online edition of the Proceedings of the National Academy of Sciences. Their findings could lead to improved cancer treatments.

Mao, an assistant professor in the UNM Division of Molecular Medicine, explains that each of our cells has proteins that enable it to carry out its tasks. DNA encodes the recipes for all of these proteins in the rungs of its ladder-like structure.

But, Mao says, “DNA is not as stable as people originally thought. It can be damaged – in other words, chemically modified.”

Cells employ several different methods to repair damage. Mao and his team, which includes scientists at UNM and at his former lab at Washington State University, studied one of these methods, called transcription-coupled DNA repair.

Transcription is the first step in a process that cells use to translate the DNA code into proteins. Inside the tiny space of a cell nucleus, DNA winds intricately on itself. To make a protein, the cell must unravel and separate the section of DNA that contains the gene sequence — the recipe — for that protein.

In transcription, a group of proteins called RNA polymerases travel along the unraveled and separated DNA, decoding the genes and building corresponding molecules called messenger RNA. Messenger RNA then travels to the cell’s protein-making structures.

During transcription, RNA polymerase will stop if it encounters a damaged section of DNA. “[It] is like a train moving on the tracks,” says Mao. “If you have damage, that’s going to block the movement of the train.”

Mao’s team discovered a choreographed sequence of cellular events that repairs the gene damage to get the RNA polymerase train moving again.

A protein called CSB goes to the stopped RNA polymerase and binds to it, dislodging a pair of proteins called SPT4/SPT5. These proteins, when bound to RNA polymerase, help it to move along the DNA during normal gene transcription. When they’re dislodged, RNA polymerase stops.

The SPT4/SPT5 release changes the shape of RNA polymerase, allowing DNA repair proteins to bind to it. With the DNA repair proteins, RNA polymerase switches from transcription to repair. Once the DNA is fixed, RNA polymerase can resume its transcription.

Mao is careful to point out that scientists don’t yet know how RNA polymerase changes back from gene-repair mode to transcribing mode. That’s an area he and his team would like to study. But, knowing more about this dance of cellular proteins, Mao says, can help make our existing cancer drug arsenal more potent.

Mao explains that by inhibiting transcription-coupled DNA repair, it is possible to sensitize cancer cells to chemotherapy and radiation therapy, which work by inducing large amounts of toxic gene damage.

“If you have robust transcription-coupled repair mechanisms and also other DNA repair pathways,” Mao says. “That will give cancer cells an advantage to survive.” So restraining cancer cells from using transcription-coupled DNA repair could make them more susceptible to the drugs and radiation.

Mao says that understanding how different proteins help or hinder this DNA repair process will help to control how cancer cells respond to chemotherapy and radiation therapy.

“We’re quite excited,” Mao says of his team’s discovery. “This gives us a lot of encouragement. There are still a lot of unanswered questions, even in this specific pathway.”

Peng Mao, PhD, is an assistant professor in the Department of Internal Medicine, Division of Molecular Medicine, at The University of New Mexico School of Medicine.

Genome-wide Role of Rad26 in Promoting Transcription-coupled Nucleotide Excision Repair in Yeast Chromatin” was published in the July 20, 2020, online edition of the Proceedings of the National Academy of Sciences. This work is a collaboration between the School of Molecular Biosciences and the Center for Reproductive Biology at Washington State University and the Department of Internal Medicine, Program in Cellular and Molecular Oncology, at The University of New Mexico Comprehensive Cancer Center. The authors are: Mingrui Duan, PhD; Kathiresan Selvam, PhD; John J. Wyrick, PhD; and Peng Mao, PhD.

The National Cancer Institute of the National Institutes of Health supported the research reported in this publication under Award Number P30CA118100, Principal Investigator: Cheryl Willman, MD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

UNM Comprehensive Cancer Center

The University of New Mexico Comprehensive Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated Cancer Center in a 500-mile radius.

Its more than 120 board-certified oncology specialty physicians include cancer surgeons in every specialty (abdominal, thoracic, bone and soft tissue, neurosurgery, genitourinary, gynecology, and head and neck cancers), adult and pediatric hematologists/medical oncologists, gynecologic oncologists, and radiation oncologists. They, along with more than 600 other cancer healthcare professionals (nurses, pharmacists, nutritionists, navigators, psychologists and social workers), provide treatment to 65% of New Mexico's cancer patients from all across the state and partner with community health systems statewide to provide cancer care closer to home. They treated approximately 14,000 patients in about 100,000 ambulatory clinic visits in addition to in-patient hospitalizations at UNM Hospital.

A total of nearly 400 patients participated in cancer clinical trials testing new cancer treatments that include tests of novel cancer prevention strategies and cancer genome sequencing.

The more than 100 cancer research scientists affiliated with the UNMCCC were awarded $35.7 million in federal and private grants and contracts for cancer research projects. Since 2015, they have published nearly 1000 manuscripts, and promoting economic development, they filed 136 new patents and launched 10 new biotechnology start-up companies.

Finally, the physicians, scientists and staff have provided education and training experiences to more than 500 high school, undergraduate, graduate, and postdoctoral fellowship students in cancer research and cancer health care delivery.

Categories: Comprehensive Cancer Center