The DNA damage dilemma

Researchers studying how cells respond to attacks come across new potential cancer target

hnRNPAug. 1, 2012 — A team of researchers in Argentina has identified a new potential target for chemotherapeutic drugs after an intense study of the molecular intricacies of cell replication and suicide.


DNA Damage-Induced Heterogeneous Nuclear Ribonucleoprotein K SUMOylation Regulates p53 Transcriptional Activation 

Background: hnRNP K acts as a p53 co-factor upon DNA damage.

Results: DNA damage stimulates hnRNP K sumoylation and this modification is required for p53 target gene expression.

Conclusion: hnRNP K sumoylation links DNA damage-induced signaling to p53 transcriptional activation.

Significance: Learning how different players within the p53 pathway are regulated will provide important insights into the study of chemotherapeutic drugs.

While there are hundreds of different types of cancer, most of them involve abnormal cell division. When the DNA inside a cell is damaged, the cell receives and sends a series of signals that determine whether the cell should stop dividing or commit suicide. If something is amiss, as in the case of cancer, those signals may not get sent or received.

The cellular response to DNA damage — which can be caused by external factors such as ultraviolet light from the sun or from internal factors such as oxidative stress — involves many proteins, two of which are the transcription factor p53 and its co-factor hnRNP K. Usually, p53 acts as a tumor suppressor that interacts with lots of molecules that help it do its job. The malfunction of p53 and its helper hnRNP K have been linked to multiple forms of cancer.

To better understand the relationship between p53 and hnRNP K and how they work together to stop abnormal cell division, the research team from the University of Buenos Aires and the National Research Council (CONICET) had to damage the cells’ DNA.

“When DNA is damaged, these two factors are stabilized,” explains Federico Pelisch, the first author on the study published in The Journal of Biological Chemistry. “That is to say that their levels are changed, and together these two molecules induce the expression of genes that are involved in the regulation of this response that will ultimately decide the fate of the cell.” Pelisch and colleagues call the cell’s two options — whether to stop dividing or to commit suicide -- “one of the cell's greatest dilemmas after DNA damage.”

The team treated human cells with a drug known to damage DNA and found that the treatment induces a change in the molecule hnRNP K. This change, biochemically is a tag that is added to hnRNP K specifically upon DNA damage, Dr. Pelisch says.

The tag is called SUMO, and it is tacked onto a specific part of hnRNP K. The process of tagging hnRNP K is, thus, called SUMOylation.

SUMOylation of hnRNP K is required for the transcription of genes involved in the DNA damage response,” Pelisch says. “And we were able to identify the exact amino acid on hnRNP K at which this modification occurs.”

The team found that, when the SUMO tag cannot be attached to hnRNP K, the DNA damage response becomes seriously impaired. In other words, the correct signals telling the cell to stop dividing or die are not sent as they should be. Disruption of this pathway may be one of the precursor events leading to cancer.

In addition, the team studied the involvement of another protein called Pc2, which had been previously linked to DNA damage, and identified it as a stimulator of hnRNP K SUMOylation.

In the paper, the authors emphasize that figuring out “how different players within the p53 pathway are regulated will provide important insights into the study of chemotherapeutic drugs.” It’s possible that drugs could one day be developed to facilitate SUMOylation if it’s not happening properly, which could restore the signals telling the cell to stop dividing or die.

Image taken from the Pelisch et al Paper in Press in JBC.