Researchers at Moffitt Cancer Center and colleagues at the University of South Florida; Duke University; Johns Hopkins University; the Brazilian National Cancer Institute; and the Rio de Janeiro Federal Institute of Education, Science and Technology have discovered that an intricate system to repair DNA damage called the "DNA damage response" (DDR) contains previously unknown components, including proteins that could be targeted as sensitizers for chemotherapy. Some of these targets may already have drugs available that have unrecognized uses in cancer therapy, said the researchers.
The study appears in the Sept. 18 issue of Science Signaling.
"A domain called BRCT is frequently present in proteins involved in the DDR network," said study lead author Alvaro N.A. Monteiro, Ph.D., senior member of Moffitt's Cancer Epidemiology Program. "We undertook a systematic analysis of the BRCT domain, a protein module that plays a critical role in the DDR, and found a large network of interacting proteins centered on BRCT-containing proteins. In doing so, we discovered new potential players in the DDR. These new players may constitute potential biomarkers for drug response or targets for treatment."
According to the authors, their data could be used to build a more comprehensive map of the components and interactions involved in the DDR, a system through which proteins detect DNA damage, promote repair and coordinate the cell cycle.
Because defects in the DDR can lead to cancer, the properly functioning network is considered to be a barrier against tumor growth. Chemotherapy regimens exploit weaknesses in the system to kill cancer cells. The new discoveries augment knowledge about the DDR by adding information on the function of specific proteins involved with BRCT-containing proteins.
"Our expectation is that the establishment of the BRCT-network will help identify potential sensitizers of therapy and accelerate the development of new therapeutic strategies," Monteiro said.
The research was supported in part by the U.S. Army Medical Research and Materiel Command, National Functional Genomics Center (W81XWH-08-2-0101), the Florida Breast Cancer Foundation, and the National Cancer Institute, part of the National Institutes of Health (P50-CA119997).
- N. T. Woods, R. D. Mesquita, M. Sweet, M. A. Carvalho, X. Li, Y. Liu, H. Nguyen, C. E. Thomas, E. S. Iversen, S. Marsillac, R. Karchin, J. Koomen, A. N. A. Monteiro. Charting the Landscape of Tandem BRCT Domain-Mediated Protein Interactions. Science Signaling, 2012; 5 (242): rs6 DOI: 10.1126/scisignal.2002255
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