08-Jan-2019 - University of California, San Diego

An errant editing enzyme promotes tumor suppressor loss and leukemia propagation

Researchers at University of California San Diego School of Medicine report that detection of "copy editing" by a stem cell enzyme called ADAR1, which is active in more than 20 tumor types, may provide a kind of molecular radar for early detection of malignancies and represent a new therapeutic target for preventing cancer cell resistance to chemotherapy and radiation.

Adenosine deaminases are a family of three enzymes encoded by the ADAR genes, which stand for adenosine deaminase acting on RNA. They regulate gene expression by modifying nucleotides within double stranded RNA molecules, serving as fundamental editors in the development of new stem cells.

The enzyme, however, is also activated in cancers as diverse as liver, breast and leukemia. A research team led by senior author Catriona Jamieson, MD, PhD, deputy director of the Sanford Stem Cell Clinical Center and deputy director of the UC San Diego Moores Cancer Center, found that the normal functions of the ADAR1 enzyme are hijacked by pre-malignant cells, leading to a cascade of molecular consequences that promote malignant transformation, dormant cancer stem cell generation and resistance to treatment.

"We were able to illuminate the abilities of ADAR1 to 'hyper-mutate' tumor suppressor RNAs in leukemia and, at the same time, edit the microRNA aimed at targeting the tumor suppressor RNA. This enzyme turns on cancer resistance via a domino effect on RNA instead of DNA," said first author Qingfei Jiang, PhD, assistant project scientist in Jamieson's lab.

Jamieson characterized RNA editing as tweaking basic genetic blueprints, not fundamentally rewriting them. Nonetheless, the results might be dramatic. "One result of detection of malignant RNA editing could be exposing dormant cancer stem cells that often escape therapies that target dividing cells, which leads to therapeutic resistance and disease relapse, and also highlight ADAR as a potentially tractable target for cancer stem cell elimination," said Jamieson.

More about UCSD
  • News

    Machine learning algorithm can't distinguish these lab mini-brains from preemie babies

    Brain organoids -- also called mini-brains -- are 3D cellular models that represent aspects of the human brain in the laboratory. Brain organoids help researchers track human development, unravel the molecular events that lead to disease and test new treatments. They aren't prefect replicas ... more

    Evonik intensifies commitment to microbiome research

    Human skin is home to a large number and wide variety of microorganisms such as bacteria, fungi, and viruses, collectively known as the skin microbiome. Its composition is as individual as a fingerprint and depends on a variety of factors. This new partnership between Evonik and the Univers ... more

    Next-generation gene drive arrives

    New CRISPR-based gene drives and broader active genetics technologies are revolutionizing the way scientists engineer the transfer of specific traits from one generation to another. Scientists at the University of California San Diego have now developed a new version of a gene drive that op ... more

  • Videos

    Researchers use acoustic waves to move fluids at the nanoscale

    A team of mechanical engineers at the University of California San Diego has successfully used acoustic waves to move fluids through small channels at the nanoscale. The breakthrough is a first step toward the manufacturing of small, portable devices that could be used for drug discovery an ... more