Identification Of A Complex Involved In Bloom Syndrome

Bloom综合征（BS）是一种罕见的人类遗传性疾病，患者表现出生长迟缓、免疫缺陷、不育、光敏性和癌症易感性。BS缺陷基因最近被克隆（命名为BLM），并被发现属于进化上保守的解旋酶家族，称为RecQ。重组BLMp蛋白已被证明具有体外解旋酶活性，这表明BS可能是由DNA代谢反应中的缺陷引起的，例如复制或修复。有趣的是，BLM基因属于解旋酶家族，就像Werner综合征和Rothmund-Thomson综合征（RTS）中突变的基因一样。这三种疾病都有一些共同的特征，如遗传不稳定和易患癌症。但每种疾病都有其独特的症状。例如，WS患者过早地表现出许多与年龄相关的特征，包括骨质疏松症、动脉粥样硬化、糖尿病和白内障，这些在BS或RTS中没有观察到。此外，WS个体不像BS患者那样表现出免疫缺陷或光敏性。为了了解这些人类疾病的分子机制，我们建议分离含有每个基因产物的蛋白质复合物。迄今为止，我们已经成功地纯化了三个多蛋白复合物含有BLM综合征基因产物（BLM）。我们能够识别这些复合物的所有成分。我们发现，这些BLM复合物含有拓扑异构酶IIIa，复制蛋白A，MLH 1，已知与BLM相互作用的蛋白质，可以刺激其解旋酶活性。我们还发现，这种复合物含有与另一种基因组不稳定性疾病范可尼贫血有关的基因产物。关于这项工作的报告已提交出版。我们目前正在研究这种复合物如何导致Bloom综合征和Fanconi贫血的机制。

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 three multiprotein complexes containing the BLM syndrome gene product (BLM). We were able to identify all components of these complexes. We found that these BLM complexes contains Topoisomerase IIIa, replication protein A, and MLH1, 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 has been submitted for publication. We are currently investigating the mechanism of how this complex contributes to both Bloom syndrome and Fanconi Anemia.