Researchers at UNC Lineberger Comprehensive Cancer Center have discovered that an enzyme called USP37 plays a crucial role in ensuring our cells copy their DNA correctly. The findings were published in Nature Communications.
The human body is made up of more than 30 trillion cells, and every day, it creates about 1 billion new cells. During this process, each cell must copy its DNA accurately, or it could lead to problems like cancer. The team found that USP37 helps control a giant cellular machine called the replisome, which acts like a molecular copy machine for DNA.
Replisome assembly and disassembly are tightly coordinated with the cell cycle to maintain genome stability, but the mechanisms remain poorly understood. Since cancer cells often disrupt normal DNA replication, the researchers aimed to uncover factors that prevent premature replisome disassembly.
“We identified USP37 as a critical protector of the DNA replication machinery during the cell cycle S phase. We showed that USP37 interacts with a part of the replisome called the CMG helicase, thereby preventing premature replisome disassembly through deubiquitination,” said Michael Emanuele, PhD, professor of pharmacology at UNC School of Medicine and UNC Lineberger. “This mechanism safeguards genome integrity and is critically important in cells that undergo oncogene-induced replication stress.”
Emanuele said the researchers believe their discovery could lead to new cancer treatments. Normal cells can survive without USP37, even though those cells might have some difficulty copying their DNA. However, cancer cells are under significant stress during that process, and the loss of USP37 is particularly detrimental. Because of this, turning off USP37 might target cancer cells while leaving healthy cells unharmed.
In addition to Emanuele, the corresponding authors are Jeanette Cook, PhD, chair and professor of biochemistry and biophysics and professor of pharmacology, and Nicholas Brown, PhD, associate professor of pharmacology at UNC School of Medicine and UNC Lineberger. The paper’s co-contributing first authors are Derek L. Bolhuis, a graduate student in the Emanuele and Brown labs; Dalia Fleifel, a graduate student in the Cook lab; and Thomas Bonacci, PhD, an assistant professor of pharmacology and member of the Emanuele lab.
“This work wouldn’t have been possible without the hard work and creativity of the first three co-authors—Derek Bolhuis, Dalia Fleifel and Thomas Bonacci—and the invaluable partnership of our collaborators Nick Brown and Jean Cook,” Emanuele said.
The researchers were supported with funding from the National Institutes of Health, National Cancer Institute, American Cancer Society, National Institute of General Medical Sciences, American Heart Association, and the University Cancer Research Fund.