HOUSTON (November 22, 2011) - In the November 18, 2011 issue of Molecular Cell, researchers from the Molecular Radiation Oncology Laboratory and Cancer Research program of The Methodist Hospital Research Institute (TMHRI) published a seminal research article that explains how mutations in a critical enzyme cause Ataxia Telangiectasia and cancer susceptibility.
In this study, led by Drs. Bo Xu, Senior Member, and Chunying Yang, Instructor, discovered a previously unknown function of the ATM protein in cell division. ATM deficiency causes a childhood neurodegenerative disease called Ataxia Telangiectasia (A-T) and a predisposition to cancer that is up to 100 times greater than in the general population. Approximately 1% of the US population carries ATM mutations, and may also have a higher risk of developing cancer- the National Cancer Institute is currently funding international studies for a definitive answer to this pressing question.
A-T is a severely debilitating disease, with patients experiencing a progressive loss of movement and speech and becoming wheelchair-bound early in life, usually before they reach adolescence. The disease is almost always fatal before the age of 30. There is no cure for A-T and available treatments focus on lessening the burden of the disease symptoms with speech and physical therapy.
In 1995, Dr. Yosef Shiloh discovered that A-T is caused by a deficiency of a protein called ATM. This lead to the rapid development of genetic testing for the diagnosis of A-T, and has opened the doors for research into possible treatments with gene therapy and other experimental methods to replace the missing protein function. At the same time, researchers around the world are trying to understand what this protein does so they can develop novel ways to approach compensating for the deficiency that is so debilitating to patients.
For decades, researchers have known that ATM plays a major role in how a cell deals with the damage that environmental radiation and toxins cause to its DNA. However, this did not clearly explain how ATM causes A-T and cancer susceptibility. The key to understanding this appears to be a novel role in cell division that was discovered by Dr. Bo Xu and colleagues, and reported in the November 18 issue of Molecular Cell. Now, we know that ATM not only is essential for DNA damage responses, but also for the progression of mitosis, the division phase of the cell growth cycle.
In the “Aurora-B Mediated ATM Serine 1403 Phosphorylation Is Required for Mitotic ATM Activation and the Spindle Checkpoint” article, Yang et al. reported that ATM stops progression of the cell cycle when errors in chromosome partitioning are discovered. This break in the cell cycle allows the cell time to fix chromosomal partitioning defects, and prevent the uneven partitioning of chromosomes to daughter cells, which is a hallmark of cancer. Yang et al. hopes that understanding how critical proteins like ATM work will allow researchers to come up with new and innovative approaches to drug development for cancer therapy. This landmark paper was an issue highlight and featured in a preview by Drs. Teeru Bihani and Philip W. Hinds in Molecular Cell.
In a second article to be published in DNA Repair, the Xu laboratory reported that another protein, Bub1, also helps to regulate both mitosis and DNA damage responses. These dual roles make ATM and Bub1 superior potential targets for cancer therapy. The researchers predict that targeting proteins which play dual roles in cell fate will advance the treatment of cancer, and be particularly effective for treating therapy resistant tumors.
This research was funded by the National Institutes of Health and The Methodist Hospital Research Institute. To speak with a representative of TMHRI, please contact David Bricker, The Methodist Hospital, at 832-667-5811 or email@example.com. For more information on The Methodist Hospital Research Institute, visit our website. Follow Methodist on Facebook and Twitter.