UNC Lineberger researchers led by Cyrus Vaziri, PhD, have made a new discovery to help explain how cancer cells overcome natural barriers to tumor progression, and tolerate stresses associated with tumor growth. In a study published in The Journal of Cell Biology, the researchers report on the role of the DNA repair protein RAD18, and associated signaling molecules, in allowing cells to tolerate oncogenic DNA replication stress.
Scientists have known that cancer-causing genes induce high levels of DNA damage, which can then actually trigger cells to stop growing, said Vaziri, a UNC Lineberger member and professor in the UNC School of Medicine Department of Pathology & Laboratory Medicine. However, this barrier to tumor progression is often imperfect, and damaged cells go on to become cancerous.
In the new study published in The Journal of Cell Biology, Vaziri and his colleagues report on how a mechanism called “trans-lesion synthesis,” which is a DNA damage-tolerant mode of DNA replication, allows cells to continue to divide despite the DNA damage they have sustained. In addition, he also said the findings reveal a new opportunity to potentially sensitize cancer cells to therapeutic DNA-damaging agents.
“These findings provide a new solution to the problem of how neoplastic cells overcome tumor suppressive barriers to cancer,” he said. “Moreover, our discovery of how selective pressure can activate trans-lesion synthesis also explains why cancer cells become resistant to DNA-damaging anti-cancer drugs.”
Vaziri was senior author of the study “DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress.” In addition to Vaziri, other authors include: Yang Yang, Yanzhe Gao, Liz Mutter-Rottmayer, Anastasia Zlatanou, Michael Durando, Weimin Ding, David Wyatt, Dale Ramsden, Yuki Tanoue and Satoshi Tateishi.