A long noncoding RNA called NORAD plays an important role in maintaining proper chromosome number in cells. NORAD loss results in aneuploidy, a hallmark of cancer cells.
A recently published study reveals an unexpected role for a long noncoding RNA (lncRNA) in maintaining the proper number of chromosomes in cells (Cell 2016;164:69–80).
Larger cousins of microRNAs, lncRNAs are transcripts of more than 200 nucleotides with no detectable open reading frames, often with unknown function. The new work shows that one lncRNA, dubbed NORAD (noncoding RNA activated by DNA damage) preserves genome stability by promoting expression of genes involved in DNA repair, replication, and mitosis. Loss of NORAD in human cells results in altered chromosome number, a hallmark of cancer cells.
Lead investigator Joshua Mendell, MD, PhD, and colleagues at the University of Texas Southwestern Medical Center in Dallas, set out to identify lncRNAs that regulate the response of cells to DNA damage. They first spotted NORAD among lncRNAs induced by treating human and mouse cells with DNA-damaging doxorubicin. Mendell's team focused on NORAD because, unlike many lncRNAs, it was abundant in many tissues, and its sequence was highly conserved between mouse and human.
To probe NORAD function, the researchers inactivated the lncRNA in a human colon cancer cell line and nontransformed human fibroblasts, revealing a surprising phenotype. “All the cells that lose this RNA exhibit a chromosomal instability phenotype, meaning that they have a high frequency of chromosome gain or loss during mitosis,” says Mendell.
The researchers went on to show that NORAD is a major binding partner for PUMILIO proteins, an ancient and highly conserved family of cytoplasmic proteins that repress translation of mRNAs. One molecule of NORAD can bind 15 PUMILIO molecules, resulting in inactivation of PUMILIO.
After DNA damage, NORAD levels are sufficient to sequester most of the cell's PUMILIO proteins, allowing beneficial expression of target genes involved in DNA replication, repair, and mitosis. In the NORAD knockout cells, increased repression of target genes by PUMILIO proteins leads to mistakes in chromosome handling and aneuploidy.
The work is the first to implicate a lncRNA as well as PUMILIO proteins in the maintenance of chromosome integrity. Whether they play a role in cancer remains to be seen, says Mendell. “We're interested in whether this pathway is perturbed in cancer, and whether it can influence cancer phenotypes,” he says. Some clues may lie in already-existing expression data from large-scale tumor genetic projects like TCGA, and his team plans to look at that, Mendell says.
The work “opens a new area of understanding of where chromosome handling might go awry,” says Maxwell Krem, MD, PhD, of the University of Louisville School of Medicine in Kentucky, who was not involved in the new study. Chromosomal instability is associated with disease prognosis and response to treatment, and attacking pathways that regulate genomic stability could become an important addition to standard chemotherapy in the future, he says. –Pat McCaffrey
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- ©2016 American Association for Cancer Research.