Howard Y. Chang, M.D., Ph.D.
Stanford University School of Medicine
An NIEHS TaRGET I grantee and colleagues discovered that a long noncoding RNA (lnc-RNA) called DINO plays a key role in helping a cell decide whether to respond to DNA damage by repairing the damage or starting the pathway towards cell death. Cellular response to DNA damage is critical for normal cell growth and cancer suppression.
Scientists are only beginning to understand the biomolecular regulatory roles of lnc-RNAs, which are commonly found throughout the genome and unlike coding RNAs don’t produce proteins. Defined as having more than 200 nucleotides, lnc-RNAs are typically precisely regulated.
The tumor suppressor protein p53 recognizes and responds to DNA damage by increasing the expression of genes involved in DNA repair and cell division. Using cell and mouse studies, the researchers found that p53 increased expression of DINO, which bound to and stabilized p53 in a positive feedback loop that amplified the p53 signal throughout the nucleus. When the researchers inhibited DINO expression, cells showed a reduced response to p53 signals. The investigators also found that when DINO expression was artificially increased, cells responded as if their DNA had been damaged even through there were no genome changes. Overall, these new findings showed that long noncoding RNA helps the cell to appropriately respond to DNA damage.
Citation: Schmitt AM, Garcia JT, Hung T, Flynn RA, Shen Y, Qu K, Payumo AY, Peres-da-Silva A, Broz DK, Baum R, Guo S, Chen JK, Attardi LD, Chang HY. 2016. An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet 48(11):1370-1376.