Researchers Identify Enzyme as a Regulator of DNA Damage Response
A team of Miller School researchers has proven that enzyme USP24 plays a strong role in regulating how cells cope with damaged DNA and prevent the development of cancer. Their findings have been published in the journal Cell Reports.
“Our laboratory focuses on studying the cellular mechanisms regulating DNA damage response and DNA repair pathways,” said Feng Gong, Ph.D., associate professor of biochemistry and molecular biology, and corresponding author of the article. “We use UV irradiation and the chemotherapeutic agent cisplatin to study how cells respond to these DNA damage agents.”
A protein known as p53 regulates the cell cycle, functioning as a tumor suppressor and preventing cancer. In more than 50 percent of cancers, however, p53 is found to have mutated. Its stability is regulated by a form of protein modification known as ubiquitination — a process that can be reversed by a group of proteins known as deubiquitinases (DUBs). Ubiquitination of p53 often leads to uncontrolled growth and the development of cancer.
“Our previous research led to the discovery that a DUB named USP24 plays a role in DNA damage response, but we did not know how that occurred,” said Gong. “The goal of our latest research was to determine if USP24 is able to reverse p53 ubiquitination.”
Through their research, the investigators learned that USP24, which itself is frequently found to be mutated in human cancers, acts as a p53 deubiquitinase. Functional USP24 is required for p53 stabilization after DNA damage. When USP24 is depleted, cells exhibit elevated mutation rates, a sign of genome instability.
“Our discovery suggests that USP24 inactivation is an alternative pathway for cancer cells with wild-type p53 to suppress p53 functions,” said Gong. “USP24-depletion leads to genome instability, thus USP24 itself appears to be a tumor suppressor.”
Now the research will move to the next step.
“We have established that USP24 can stabilize wild-type p53 in cells by removing the ubiquitin modification that induces its degradation,” said Gong. “But does USP24 stabilize mutant p53? One mystery in the p53 field of research is that mutant p53 is usually overexpressed in tumor samples, but the mechanism responsible for this phenotype is not clear. We need to examine if increased expression of USP24 is responsible for increased mutant p53 expression in human cancers. Future studies, such as with USP24 knockout mice, are needed to establish the physiological role of USP24 in tumorigenesis.”
Additional authors of the article include Ling Zhang, Ph.D., associate scientist; Leah Nemzow, Ph.D. candidate; Hua Chen, Ph.D., post-doctoral fellow; Abigail Lubin, Ph.D. candidate; and Thomas K. Harris, Ph.D,, associate professor, all in the Department of Biochemistry and Molecular Biology; Zhongyi Sun, M.D., Ph.D., a former visiting professor from Daping Hospital at Third Military Medical University in Chongqing, China; and Xi Rong, an M.D. student from Peking Union Medical College in Beijing, who did summer research in Gong’s laboratory.