Yin Jinhu, Sobeck Alexandra, Xu Chang, Meetei Amom Ruhikanta, Hoatlin Maureen, Li Lei, Wang Weidong
Laboratory of Genetics, National Institute on Aging, National Institute of Health, Baltimore, MD 21224, USA.
EMBO J. 2005 Apr 6;24(7):1465-76. doi: 10.1038/sj.emboj.7600622. Epub 2005 Mar 17.
Bloom's syndrome (BS) is a rare human genetic disorder characterized by dwarfism, immunodeficiency, genomic instability and cancer predisposition. We have previously purified three complexes containing BLM, the helicase mutated in this disease. Here we demonstrate that BLAP75, a novel protein containing a putative OB-fold nucleic acid binding domain, is an integral component of BLM complexes, and is essential for their stability in vivo. Consistent with a role in BLM-mediated processes, BLAP75 colocalizes with BLM in subnuclear foci in response to DNA damage, and its depletion impairs the recruitment of BLM to these foci. Depletion of BLAP75 by siRNA also results in deficient phosphorylation of BLM during mitosis, as well as defective cell proliferation. Moreover, cells depleted of BLAP75 display an increased level of sister-chromatid exchange, similar to cells depleted of BLM by siRNA. Thus, BLAP75 is an essential component of the BLM-associated cellular machinery that maintains genome integrity.
布卢姆综合征（BS）是一种罕见的人类遗传性疾病，其特征为侏儒症、免疫缺陷、基因组不稳定和癌症易感性。我们之前已经纯化了三种含有BLM的复合物，BLM是在这种疾病中发生突变的解旋酶。在此，我们证明，BLAP75是一种含有假定OB折叠核酸结合结构域的新型蛋白质，是BLM复合物的一个组成部分，并且对其在体内的稳定性至关重要。与在BLM介导的过程中发挥的作用一致，BLAP75在DNA损伤时与BLM共定位于核内亚结构域，并且其缺失会损害BLM募集到这些亚结构域。通过小干扰RNA（siRNA）耗尽BLAP75也会导致有丝分裂期间BLM磷酸化不足，以及细胞增殖缺陷。此外，耗尽BLAP75的细胞显示出姐妹染色单体交换水平增加，类似于通过siRNA耗尽BLM的细胞。因此，BLAP75是维持基因组完整性的BLM相关细胞机制的一个重要组成部分。
