Ionizing radiation (IR), produced by certain minerals in the Earth, represents a major environmental health hazard to man because it causes DNA double-strand breaks (DSBs), highly toxic DNA lesions that often result in genome instability and cancer. It is well established that chromosomal translocations at DSBs can promote lymphoma development. However, there still remains a significant gap in the knowledge of regulatory mechanisms of the repair DNA DSBs induced by IR and lymphoma suppression. The BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) is a conserved protein with chimeric ubiquitin-protein conjugase (E2) and ligase (E3) activities that catalyze post-translational modification of proteins by ubiquitin. Until recently, BRUCE has only been shown to be involved in apoptosis inhibition, cytokinesis, and mouse embryogenesis. Recently, our preliminary studies provide the first indication that BRUCE is a suppressor of lymphoma and a regulatory protein in DNA-repair pathways. In particular, we observed that BRUCE mice are susceptible to lymphomas, and that cells with BRUCE inactivated display genomic instabilities and unrepaired DSBs following ionizing radiation. We also observed that BRUCE acts at a step upstream in DNA-repair cascade by regulating the accumulation, at the site of the DSB, of early DNA-damage signaling proteins and downstream repair proteins following IR. Furthermore, BRUCE has strong relevance to human health in that a reduction in the level of BRUCE gene expression is associated with human lymphomas and also correlates with low survival of lymphoma patients. Based on these findings, we hypothesize that BRUCE suppresses chromosomal abnormalities and lymphomagenesis by promoting DNA DSB repair. We propose two aims to test this hypothesis: (1) To determine chromosomal translocations in lymphomas developed in our heterozygous BRUCEWT/C mutant mice, and whether they are resulted from compromised repair of programmed and/or general DSBs in lymphocytes. We will also determine whether reduced levels of BRUCE protein are associated with lymphoma development by analyzing human lymphoma tissue array. (2) To determine the mechanism by which BRUCE regulates access of repair proteins to the sites of DSB and its implication in DSB-repair pathways of homologous recombination (HR) and non-homologous end joining (NHEJ, both classic and alternative). This proposed work is significant because it will be the first indication that BRUCE is a suppressor of lymphoma and a regulatory protein in DNA repair. This work is also innovative because it has never been expected or even speculated that BRUCE, an anti-apoptosis protein, could regulate DNA repair and tumor suppression. It challenges the current ubiquitin paradigm by placing BRUCE upstream of the current ubiquitin regulatory pathway. These results are expected to lay the groundwork for developing novel agents capable of modulating the level and/or the activity of BRUCE for innovative intervention of lymphoma other related diseases resulting from faulty DNA repair.
The proposed research is relevant to public health because the discovery of novel regulatory mechanisms for lymphoma suppression and for ionizing radiation-induced DNA damage repair are ultimately expected to improve our understanding of the pathology and etiology of lymphoma and of other malignancies in general. Therefore, the proposed work is relevant to the part of NIH's mission for opening new avenues for developing therapeutic strategies aimed at eliminating lesions that lead to the initiation, maintenance, and progression of cancer.
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