Environmental Factor

Environmental Factor

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November 2016

RNA molecule regulates cellular response to DNA damage

A newly identified RNA molecule called DINO can control a cell’s response to DNA damage by physically binding with a protein called p53, according to Stanford researchers partly funded by NIEHS. The research team, led by Howard Chang, M.D., Ph.D., observed a positive feedback loop between p53 and DINO that determines how a cell should respond to DNA damage — specifically, whether to repair the damage or trigger cell death. Their findings were published Sept. 26 in the journal Nature Genetics.

DINO, short for Damage Induced Noncoding, is considered a long noncoding RNA (lncRNA) because it does not encode for a protein. The role of lncRNAs in p53 regulation has been unclear. The results from this study, which are consistent in both human and mouse cells, reveal a new role for lncRNAs in coordinating cell outcomes through direct RNA-protein interaction.

The p53 DNA damage response

The p53 protein serves as a master regulator of the DNA damage response. When a cell sustains DNA damage, p53 activates a number of target genes, depending on the severity of the damage. The products of these genes contribute to either DNA repair, halting the cell cycle, or triggering cell death. Minor DNA damage may be repaired, but serious damage often results in p53-mediated cell death, or apoptosis, as a safeguard to avoid tumor development. For this reason, p53 is considered a tumor suppressor.

The study’s authors explained that under normal circumstances, p53 is continuously degraded to maintain levels too low to activate its target genes. However, after DNA damage, p53 is stabilized by processes that modify the protein and slow down its degradation. This causes levels of p53 to accumulate, so it can activate its target genes.

“If p53 remains destabilized, DNA damage signaling [and] response won’t occur,” said Fred Tyson, Ph.D., program director in the NIEHS Department of Extramural Research and Training. “This includes apoptosis triggered by DNA damage. If that apoptosis doesn’t occur, tumors are more likely to develop.”

Tyson noted that Chang was funded under a grant program, called TaRGET I, for studies of how DNA transcription is affected by exposures to toxicants.

Amplifying this response

Chang’s study found that among the human cells tested, those with sufficient p53 increased their levels of DINO after treatment with doxorubicin, a DNA-damaging agent that is widely used in chemotherapy. Cells without enough p53 did not induce DINO after DNA damage. Conversely, depleting DINO decreased the activation of many p53 target genes, suggesting that p53 and DINO feed positively into one another.

“DINO expression allows the cell to fine-tune its response to DNA damage and respond appropriately,” Chang stated in a Stanford press release. The study’s positive feedback model proposes that DINO levels increase after DNA damage. This leads to stabilization of p53 levels, which in turn amplifies the DNA damage response, in keeping with the severity of damage.

Binding sites discovered

The researchers found a major p53-binding site in DINO, indicating that DINO and p53 may physically bind. Moreover, DINO was found at the p53-binding elements of several p53 target genes, suggesting that DINO and p53 interact at many of the genes involved in the DNA damage response. These target genes include one called CDKN1A, also known as p21, which encodes for a protein that causes cell cycle arrest. Halting the cycle allows time for DNA repair.

The authors also reported that DINO can make cells more sensitive to irradiation, another important process previously associated with p53. The findings suggested that DINO serves an important function in initiating cell death and potentially avoiding the development of tumors.

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 J, Attardi LD, Chang HY. 2016. An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet (48)1370–1376.

(Emily Mesev is an Intramural Research Training Award postbaccalaureate fellow in the NIEHS Intracellular Regulation Group.)


DINO GFP

Researchers engineered cells to glow green when trying to make DINO then exposed some to doxorubicin. The image on the right shows them responding to the DNA damage. (Photo courtesy of Julia Garcia, Stanford University)

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