Project Details


One of the earliest-described hallmarks of cancer cells is an aberrant presentation of their genetic material. Genomic instability, defined as the ability of cancer cells to acquire genetic mutations with much higher frequency than normal cells, enables them to inactivate cellular mechanisms that would normally keep in check cell division and growth and became cancerous. Cells normally resist genetic instability by employing a number of mechanisms and pathways, collectively known as DNA repair, that constantly scan the DNA looking for lesions or mutations and quickly restore the original sequence when such an event is detected. The staggering array of DNA repair molecules that each cell is equipped with bears evidence of the important role that DNA repair has in suppressing tumorigenesis. Not surprisingly, DNA repair pathways are themselves the first targets of mutation in cancer cells. Like a snowball effect, once a DNA repair mechanism is inactivated by mutations, cells lose some of their ability to repair damage and more and more mutations accumulate, disabling further protection mechanisms until cellular transformation and cancer occurs. Indeed, almost all cancer types have been associated with mutations in DNA repair genes. In one of the best-known examples, inactivating mutations in BRCA1 and BRCA2 genes, involved in a DNA repair mechanism termed homologous recombination, have been shown to cause cancer in a staggering 70% of women carrying this mutation by promoting genomic instability. Genomic instability can also occur because of exposure to environmental carcinogens. Radiation exposure is a well-known military risk factor. Radiation creates DNA damage, which, if incorrectly repaired, can lead to mutations, genomic instability, and carcinogenesis. In particular, radiation exposure results in increased incidence of leukemia. Our laboratory has a long-standing interest in investigating such mechanisms that promote genomic stability and how they are important in inhibiting cancer formation. We recently identified a novel mechanism that regulates homologous recombination and genomic stability in human cells. We discovered a new protein, which we named PARI, which is able to regulate BRCA2 activity during DNA replication. We found that PARI promotes cancer by allowing cancer cells to efficiently remove DNA damage that spontaneously appears in cancer cells due to their increased metabolism and proliferation rates. In particular, we found that PARI is important for survival of leukemia cells, suggesting that drugs targeting PARI might be efficiently used in leukemia therapy. Here, we plan to study the detailed mechanism of how PARI promotes leukemia. Our laboratory has already made substantial contributions to cancer research topic areas of cancer genetics and cancer related to radiation exposure by identifying cellular mechanisms that control DNA repair and are dysregulated in cancer. Successful completion of this study will allow us to demonstrate that PARI is universally employed by solid and blood cancer cells to promote increased proliferation and growth and thus put us at the forefront of cancer research. The research plan and the career development plan are carefully crafted to ensure that the most recent cancer research techniques are employed (next-generation sequencing, specialized repair assays, animal cancer models), that alternative hypothesis are considered, and that careful mentoring is in place to allow the overcome of any obstacles encountered during the proposed research. In the long term, this research will allow us to obtain drugs that can protect against and treat leukemia. Thus, this research will help leukemia patients by providing them with novel therapies. This research will also study if PARI expression represents a novel biomarker that predicts the response of leukemia cells to currently available therapy. Thus, this research will allow a more rational use of availab
Effective start/end date9/15/15 → …


  • U.S. Army: $569,841.00


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.