Cancer drug discovery: Targeting DNA repair
Woodruff Health Sciences Center | Aug. 23, 2017
The SAMHD1 protein, seen here as green spots, localizes to sites of DNA damage in cancer cells exposed to radiation.
From Daddacha et al. Cell Reports (2017).
Standard anticancer treatments, such as chemotherapy, target rapidly dividing cells by damaging their DNA. A newer strategy is to undercut cancer cells' ability to repair DNA damage.
Winship Cancer Institute investigators led by David Yu, MD, PhD have identified a distinct function in DNA double strand break repair for an enzyme called SAMHD1. Depleting or inhibiting SAMHD1 could augment anticancer treatments that induce DNA double-strand breaks, such as ionizing radiation or PARP inhibitor drugs, they suggest. Ionizing radiation is a mainstay of cancer treatment and PARP inhibitors are being developed for several cancer types.
The findings were published this week in Cell Reports (open access).
SAMHD1 was known for its ability to chop up the building blocks of DNA, and had come to the attention of virologists because it limits the ability of retroviruses such as HIV to infect some cell types. The first author of the paper, postdoc Waaqo Daddacha, PhD, previously studied SAMHD1 with virologist Baek Kim, PhD, professor of pediatrics.
Cancer researchers had already sought to harness a retroviral protein called Vpx, which viruses evolved to disable SAMHD1. Acute myeloid leukemia cells use SAMHD1 to get rid of the drug cytarabine, so Vpx can sensitize AML to that drug. The Cell Reports paper shows that virus-like particles carrying Vpx could be deployed against other types of cancer, in combination with agents that induce DNA double-strand breaks.
In addition, Daddacha, Yu and their colleagues discovered that SAMHD1 is involved in processing the damaged ends of chromosomes, independently of its chopping function. Other drugs could potentially target that processing role. The scientists showed that SAMHD1 appears at sites of DNA damage in cells and interacts with other DNA repair proteins.
Mutations in the gene encoding SAMHD1 have been observed in some forms of leukemia and colorectal cancer. One such mutation in SAMHD1 disrupted the interaction with the other repair factors. SAMHD1 mutations, along with mutations in several other genes, also cause Aicardi-Goutieres syndrome, an autoimmune disorder.
Yu is associate professor of radiation oncology at Winship Cancer Institute and Emory University School of Medicine. Co-author Kim is director of the Center for Drug Discovery, part of the Emory-Children's-Georgia Tech Research Alliance.
Winship co-authors include Paul Doetsch, PhD, Distinguished Chair and Associate Director for Basic Research, William Dynan, PhD, professor of radiation oncology and a Georgia Research Alliance Eminent Scholar, Xingming Deng, PhD associate professor radiation oncology, and Ya Wang, PhD, professor of radiation oncology.
Research in Yu's lab was supported by the National Cancer Institute (R01CA178999, R01CA178999S1) and the Department of Defense (CA160771).