Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome

Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome.布卢姆综合征（Bloom syndrome）是一种隐性人类遗传性疾病，兼具基因组不稳定性、生长发育缺陷与癌症易感性表型。目前已知的唯一致病基因为BLM解旋酶（BLM helicase），该蛋白与拓扑异构酶IIIα（topoisomerase III alpha）、RMI1及RMI2共同组成蛋白质复合物，可维持复制叉稳定性并解离双霍利迪连接体（double Holliday junctions），从而防止基因组不稳定性的发生。本研究首次鉴定出第二个致病基因RMI2，该基因在携带布卢姆样表型的受累同胞中存在缺失。纯合突变个体来源的细胞表现出姐妹染色单体交换（sister chromatid exchange）频率升高、分裂后期DNA桥及微核（micronuclei）数量增多的特征。在独立构建的RMI2基因敲除细胞（knockout cells）中也观察到了类似的基因组与染色体不稳定表型。无论是患者来源细胞还是基因敲除细胞系，均可观察到BLM向超细微DNA桥（ultra fine DNA bridges）的定位减少，以及范科尼贫血互补组D2蛋白（FANCD2）在桥连接焦点（foci）处的募集水平降低。综上，RMI2的缺失会导致BLM复合物活性部分受损，进而引发表型温和的布卢姆综合征。