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 the genes 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 BLM syndrome gene product (BLM). We were able to identify most of the components of this complex. We found that the BLM complex contains Topoisomerase IIIa and replication protein A, proteins which are known to interact with BLM and could stimulate its helicase activity. We also found that this complex contains gene products involved in another genome instability disease, Fanconi Anemia. A report on this work is currently being revised for Nature Genetics. We are currently investigating the possibility that this complex contributes to both Bloom syndrome and this new genome instability disease.
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