March 2016 NUI Galway Scientists Discover How A Protein Helps To Prevent Cancer

An NUI Galway study discovers how the protein USP9X contributes to the duplication of genetic information and protects from the development of cancer

A young team of researchers led by Professor Corrado Santocanale from the Centre for Chromosome Biology at NUI Galway, in collaboration with the prestigious IFOM Research Institute in Milan, Italy, have discovered that a protein named USP9X contributes to the efficient duplication of the DNA in cells. The study has been published in the international journal Cancer Research.

The main feature of all cancer cells is uncontrolled growth and duplication. Many drugs used in treating cancer prevent DNA replication thereby stopping the cancer cell from dividing. At the same time, in normal cells, the coordination of the multiple processes that allow DNA replication to be extremely accurate, is key for maintaining genome stability and preventing cancer.

At the molecular level, the research scientists found that USP9X binds to a key replication protein and prevents it from being destroyed. The study found that when the function of USP9X is compromised, the machinery (a large number of proteins and enzymes that work together) that duplicates the DNA becomes unstable. And for this reason, the cells accumulate DNA damage and are more sensitive to genotoxic stress (the property of chemical agents that damages the genetic information within a cell causing mutations, which may lead to cancer) including anti-cancer drugs that act by impairing DNA synthesis.

USP9X is a well-known player in the cancer arena and previous research has indicated its involvement in multiple cancer-relevant signaling and survival pathways. Intriguingly, and in a context dependent manner, USP9X can be considered either as a factor that protects from the development of the disease or, when the disease is already established, as a potential point of intervention for novel anti-cancer drugs.

CLASPIN, a protein that is important during the process of the duplication of the DNA, must be tightly regulated during the cell cycle to prevent the accumulation of DNA damage. In this study, the NUI Galway and IFOM research team used a sophisticated technology to detect molecular associations and identified USP9X as a novel CLASPIN binding protein.

Professor Corrado Santocanale from the School of Natural Sciences at NUI Galway, and lead author of the study said: “We found that USP9X regulated the expression and stability of CLASPIN when cells duplicate their DNA. Our PhD student, Edel McGarry carried out most of the laboratory experiments and found USP9X depletion profoundly impairs the progression of DNA replication forks, causing unscheduled termination events with a frequency similar to CLASPIN depletion, resulting in excessive DNA damage.”

Professor Corrado added, “Importantly, restoration of CLASPIN expression in USP9X-depleted cells partially suppressed the accumulation of DNA damage. Furthermore, USP9X depletion compromised the normal signals that occur in the cells when they are exposed to DNA replication inhibitors or UV radiation, promoting hypersensitivity to drug-induced replication stress. Taken together, our results reveal a novel role for USP9X in the maintenance of genomic stability during DNA replication, and provide potential mechanistic insights into its tumor suppressor role in certain malignancies.”

To read the full Cancer Research paper visit: http://cancerres.aacrjournals.org/content/early/2016/03/02/0008-5472.CAN-15-2890.abstract

ENDS