A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome
A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome
复制标题
DOI：
10.1128/mcb.23.10.3417-3426.2003
复制
发表时间：
2003-05-01
影响因子：
5.3
通讯作者：
Wang, WD
中科院分区：
文献类型：
--
作者：
Meetei, AR;Sechi, S;Wang, WD
布卢姆综合征（BS）是一种遗传性疾病，与侏儒症、免疫缺陷、生育能力下降和癌症风险升高有关。为了探讨该疾病的发病机制，我们从人HeLa中分离出三个含有BS、BLM中解旋酶缺陷的复合物。有趣的是，其中一种称为BRAFT的复合物也含有5种范可尼贫血（FA）互补基团蛋白（FA蛋白）。FA在基因组不稳定性和癌症易感性方面与BS相似，但其大部分基因产物没有已知的生化活性，并且该疾病的分子发病机制尚不清楚。BRAFT显示出dna解绕活性，这需要BLM的存在，因为从BLM缺陷细胞中分离的复合物缺乏这种活性。该复合物还含有拓扑异构酶iii α和复制蛋白A，这些蛋白质已知与BLM相互作用，可以促进DNA的解绕。我们发现从FA细胞系中分离的BLM复合物具有较低的分子质量。我们的研究首次提供了多蛋白FA复合物的生化表征，并提示了基因组维持的BLM和FA途径之间的联系。FA蛋白是DNA解绕复合体的一部分，这一发现意味着FA蛋白可能参与DNA修复。
Bloom syndrome (BS) is a genetic disorder associated with dwarfism, immunodeficiency, reduced fertility, and an elevated risk of cancer. To investigate the mechanism of this disease, we isolated from human HeLa extracts three complexes containing the helicase defective in BS, BLM. Interestingly, one of the complexes, termed BRAFT, also contains five of the Fanconi anemia (FA) complementation group proteins (FA proteins). FA resembles BS in genomic instability and cancer predisposition, but most of its gene products have no known biochemical activity, and the molecular pathogenesis of the disease is poorly understood. BRAFT displays a DNA-unwinding activity, which requires the presence of BLM because complexes isolated from BLM-deficient cells lack such an activity. The complex also contains topoisomerase IIIalpha and replication protein A, proteins that are known to interact with BLM and could facilitate unwinding of DNA. We show that BLM complexes isolated from an FA cell line have a lower molecular mass. Our study provides the first biochemical characterization of a multiprotein FA complex and suggests a connection between the BLM and FA pathways of genomic maintenance. The findings that FA proteins are part of a DNA-unwinding complex imply that FA proteins may participate in DNA repair.