Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Structure. 2010 Sep 8;18(9):1159-70. doi: 10.1016/j.str.2010.06.008.
Mutations in BLM, a RecQ-like helicase, are linked to the autosomal recessive cancer-prone disorder Bloom's syndrome. BLM associates with topoisomerase (Topo) IIIα, RMI1, and RMI2 to form the BLM complex that is essential for genome stability. The RMI1-RMI2 heterodimer stimulates the dissolution of double Holliday junction into non-crossover recombinants mediated by BLM-Topo IIIα and is essential for stabilizing the BLM complex. However, the molecular basis of these functions of RMI1 and RMI2 remains unclear. Here we report the crystal structures of multiple domains of RMI1-RMI2, providing direct confirmation of the existence of three oligonucleotide/oligosaccharide binding (OB)-folds in RMI1-RMI2. Our structural and biochemical analyses revealed an unexpected insertion motif in RMI1N-OB, which is important for stimulating the dHJ dissolution. We also revealed the structural basis of the interaction between RMI1C-OB and RMI2-OB and demonstrated the functional importance of the RMI1-RMI2 interaction in genome stability maintenance.
BLM 基因突变与常染色体隐性遗传的癌症易感性疾病 Bloom 综合征有关。BLM 与拓扑异构酶 (Topo) IIIα、RMI1 和 RMI2 结合形成 BLM 复合物，对于基因组稳定性至关重要。RMI1-RMI2 异二聚体刺激双链 Holliday 结解旋为 BLM-Topo IIIα 介导的非交叉重组体，对于稳定 BLM 复合物至关重要。然而，RMI1 和 RMI2 的这些功能的分子基础仍不清楚。在这里，我们报告了 RMI1-RMI2 的多个结构域的晶体结构，直接证实了 RMI1-RMI2 中存在三个寡核苷酸/寡糖结合 (OB) 折叠。我们的结构和生化分析揭示了 RMI1N-OB 中一个意想不到的插入模体，该模体对于刺激 dHJ 解旋非常重要。我们还揭示了 RMI1C-OB 和 RMI2-OB 之间相互作用的结构基础，并证明了 RMI1-RMI2 相互作用在维持基因组稳定性方面的功能重要性。
