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Ever since graduate school, ӳ����ý associate member John Rinn has been determined to understand the function of genes known as large intergenic non-coding RNAs (or “lincRNAs.”) Once dismissed as meaningless filler in the genome, more than a thousand lincRNAs have recently been uncovered, and many play a critical role in cell development and regulation.

Now, Rinn, ӳ����ý postdoctoral researcher Maite Huarte, and colleagues have added a new chapter to the story. In the August 6 issue of the journal Cell, researchers at the ӳ����ý and Beth Israel Deaconess Medical Center (BIDMC) report that dozens of lincRNAs are activated by p53, a tumor suppressor protein.

Since the central role of the p53 gene in cancer was first described more than 30 years ago, thousands of scientific articles have been published describing the way it regulates cell cycle and cell death in response to DNA damage. In fact, researchers nicknamed the p53 tumor suppressor protein encoded by the gene “the guardian of the genome” because cells that have lost p53 function can divide and replicate unchecked. Yet the guardian may still have a new weapon in its arsenal.

“It was very intriguing to me why the genome would produce these RNAs that don’t seem to have a  protein coding capacity,” said Huarte, first author of the paper. “However, they are expressed with very specific patterns, sometimes correlating with oncogenic pathways, and are conserved through evolution, so there must be a reason why they’re there.”

The researchers found that several dozen lincRNAs are targeted directly by p53. One gene in particular, lincRNA-p21, responds to signals from p53 by suppressing multiple genes across the genome to prompt cell death, or apoptosis.

“We think that lincRNA-p21 may represent a new class of ‘tumor suppressor lincRNAs,’” said Rinn, senior author of the paper, who is also an assistant professor of pathology at BIDMC and Harvard Medical School. “These findings may lead to the identification of novel biomarkers and targets for anti-cancer therapies, as well as add to our understanding of the mechanisms of gene regulation by lincRNAs.”

Huarte, who has long been interested in how gene expression is regulated in the context of cancer, explained, “We were surprised to find that lincRNA-p21 appears to be functioning as a global repressor, regulating hundreds of genes in the p53 pathway. This lincRNA is playing defense for p53 to block other pathways in their efforts to interfere with p53’s critical job of tumor suppression by cell death.”

Rinn, Huarte, and the other researchers found that lincRNA-p21 carries out this function by playing air-traffic controller, roping in other critical factors in the cell’s nucleus to help tamp down specific genes. “In the same way that air traffic controllers organize planes in the air, lincRNAs organize key nuclear complexes in the cell,” said Rinn. “lincRNA-p21 specifically binds to a protein called hnRNP-K, and then guides hnRNP-K to its final destination to shut down any genes that interfere with p53.”

While lincRNAs are important for unraveling the mysteries of cancer, they also have broad implications for understanding the biology of many other diseases. “We know that so-called ‘transcription factors’ can turn genes on by recruiting transcriptional machinery,” Rinn said, “but it has been less clear how they turn genes off. lincRNAs could be those elusive ‘anti-factors’ that serve to shut genes down by reshuffling proteins around the genome.”