S-Phase Dynamics of the Mre11 Complex as a Barrier to Cancer
Abstract
The cell division cycle is the highly regulated process by which a cell grows, duplicates its DNA, and divides to give two daughter cells. One of the initiating factors in cancer is an increase in growth signals to the cell. These growth signals cause cells to rapidly progress through the cell division cycle in an unregulated and uncontrolled manner. This ?rushing? through the cell cycle leads to an increase in errors being made during DNA duplication. If these errors remain, they lead to changes in the DNA sequence, known as mutations, which are subsequently passed onto the daughter cells. Accumulation of mutations leads to a healthy cell becoming a cancerous one. To prevent mutations, and thus cancer, from occurring, the cell has a network of proteins collectively known as the DNA damage response. It is the job of the DNA damage response to identify DNA that has been damaged due to mistakes during its duplication and to either repair the damage, or if the damage is irreparable, eliminate the cell. A mutation that prevents the DNA damage response from working correctly can therefore have disastrous consequences. The Mre11 complex, consisting of the Mre11, Rad50, and Nbs1 proteins, is a key component of the DNA damage response. A study involving the Petrini lab looked at the DNA sequence of 7,494 tumors across 28 different tumor types and found the Mre11 complex to be mutated in 4% of tumors, many of which are from cancers listed in the Fiscal Year 2016 Peer Reviewed Cancer Research Program topic areas. Interestingly, the cancer type in which the Mre11 complex is most commonly mutated is bladder cancer. Eleven percent of the bladder tumors had a mutation within the Mre11 complex. This is a significant number, as an estimated 76,960 adults will be diagnosed with bladder cancer this year in the United States. The Petrini lab studied one of these tumors in more detail. They found that the Mre11 complex mutation was present in 100% of the cancer cells, meaning it was likely one of the causes of the bladder cancer. Furthermore, a number of studies have shown that mutation of the Mre11 complex can have a direct bearing on the outcome of bladder cancer treatment. Despite all of this, little is known about the mechanisms by which the Mre11 complex prevents against bladder cancers or what cellular processes go wrong when it is mutated. Working at Memorial Sloan Kettering Cancer Center (MSKCC), the world?s leading cancer center, means we have access to the DNA sequence information from tens of thousands of patient?s tumors. We will therefore use this information to take Mre11 complex mutations found in bladder cancer and model them in the lab using yeast and mouse cells. This system will enable us to understand which Mre11 complex mutations are important to bladder cancer, understand which pathways and networks the Mre11 complex functions in to prevent bladder cancer, identify other proteins that may also be important in bladder cancer, and test how best to treat bladder cancers with Mre11 complex mutations. The data from this study will allow doctors to identify patients whose cancers have clinically relevant Mre11 complex mutations and give them the treatment that is most likely to succeed. This study can therefore have an impact in the clinic within a very short period of time and lead to a significant increase in the survival rates of military personnel and their families who are suffering from bladder cancer or other cancers that display Mre11 complex mutations. In fact, a previous study by the Petrini lab using a yeast and mouse cell approach, in collaboration with doctors at MSKCC, Cornell Medical School, and the University of California, San Francisco, has already led to the survival of one patient with an otherwise unresponsive Mre11 complex mutated bladder cancer. My overall career goal is to become an independent researcher studying the role of the DNA damage response in cancer, with the ultimate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710391
Entities
People
- Christopher P Wardlaw
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army