Bloom syndrome (BS) is a rare human genetic disease in which patients exhibit growth retardation, immunodeficiency, infertility, photosensitivity, and predisposition to cancer. The gene defective in BS has recently been cloned (named BLM) and was found to belong to an evolutionarily conserved helicase family, called RecQ. The recombinant BLMp protein has been shown to possess a helicase activity in vitro, suggesting that BS could be caused by a defect in a DNA metabolic reaction, such as replication or repair. Interestingly, BLM gene belongs to the helicase family, like those mutated in Werner Syndrome and Rothmund-Thomson syndrome (RTS). All three diseases have some common features, such as genetic instability and predisposition to cancer. But each disease has its own distinctive symptoms. For example, WS patients prematurely display many age-related features, including osteoporosis, atherosclerosis, diabetes and cataracts, which are not observed in BS or RTS. Also, WS individuals do not show immunodeficiency or photosensivity like BS patients. To understand the molecular mechanism of these human diseases, we propose to isolate the protein complexes containing each gene product. To date, we have successfully purified a multiprotein complex containing the WS gene product. Characterization of this complex has enabled us to realize that the WS gene product could participate in a specific DNA repair process and its subsequent signaling pathway. In this proposed work, we would like to use the same approach to isolate the complex containing BLM. Preliminary data suggest that BLM is also present in a complex with several other proteins. Characterization of this complex is currently under way.
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