Protein’s role in genetic repair revealed
Examining basic cellular processes, USC researchers have discovered how an anti-tumor protein plays an important role in activating the process of repairing damaged DNA and a direct role in maintaining chromosomal stability.
With chromosomal chaos long being linked to cancer, the findings are expected to help researchers eventually develop cancer-fighting tools.
Chengyu Liang, assistant professor of molecular microbiology and immunology at the Keck School of Medicine of USC, is the corresponding author for a paper published online on April 26 in the journal Developmental Cell. Also contributing significantly to the research were first author Zhen Zhao, a USC postdoctoral fellow in Liang’s laboratory, and Soohwan Oh, a former technician in the lab and currently a doctoral student at the University of California, San Diego.
The research unveiled a new role for the protein U.V. irradiation resistance-associated gene (UVRAG), which is at work during the routine cellular self-cleaning and recycling process called autophagy.
“Basically, UVRAG acts as a scaffold or adaptor protein by binding to and activating the DNA-dependent protein kinase [DNA-PK] enzyme,” Liang said. “When there is a double-strand break, one of the most severe types of DNA damage, DNA-PK fixes the damage through a kind of gluing process.”
Conversely, Liang said, when UVRAG is removed from the cells, DNA-PK activity is impaired or reduced.
“As a result, the cells can’t repair damaged DNA in a timely and accurate manner, and this damage accumulates in cells, which results in structural alterations of the chromosomes and enables tumors to grow.”
Liang and co-investigators previously identified UVRAG as a tumor suppressor that activates the autophagy pathway in cells. The researchers found that UVRAG plays a critical role in both early and late stages of autophagy, which rids cells of toxins, viruses and bacteria.
With the latest study, which was funded by grants from the National Institutes of Health, the American Cancer Society and the Baxter Foundation, the researchers also discovered that UVRAG helps to stabilize the number of centrosomes – specialized structures in the cell that play an important role in cell division.
“We found that UVRAG helps to maintain the correct number of centrosomes and that if it is deleted or reduced, the centrosomes multiply and duplication during cell division becomes out of control,” Liang said. “As a result, the genetic material can’t equally divide into daughter cells, and the number of chromosomes will change to either too many or too few.”
When that happens, it causes problems with growth, development and functions of the cell’s system, the researcher said.
“UVRAG seems to be new cells’ guardians,” she added, “keeping an eye on our DNA and centrosomes, fixing damage and preventing improper cell division. So this study represents a major conceptual advance in understanding UVRAG’s role as an autophagy-related protein in the suppression of cancer while at the same time unfolding elegant mechanisms whereby UVRAG acts to maintain genomic integrity.”
Liang said that future research will focus on an in-depth analysis of how UVRAG maintains the integrity of centrosomes, how UVRAG’s dual roles during DNA damage repair and cell division are coordinated and how UVRAG’s role in autophagy is related to these dual roles.
“Ultimately,” Liang said, “we may be able to understand whether UVRAG helps in cancer chemotherapy or affects cancer cells’ responses to the drugs. We also may be able to determine by the level of UVRAG that is present whether a patient will or will not respond to chemotherapy.”