The BLM-TOP3A-RMI1-RMI2 proximity map reveals that RAD54L2 suppresses sister chromatid exchanges

Homologous recombination is a largely error-free DNA repair mechanism conserved across all domains of life and is essential for the maintenance of genome integrity. Not only are the mutations in homologous recombination repair genes probable cancer drivers, some also cause genetic disorders. In particular, mutations in the Bloom (BLM) helicase cause Bloom Syndrome, a rare autosomal recessive disorder characterized by increased sister chromatid exchanges and predisposition to a variety of cancers. The pathology of Bloom Syndrome stems from the impaired activity of the BLM-TOP3A-RMI1-RMI2 (BTRR) complex which suppresses crossover recombination to prevent potentially deleterious genome rearrangements. We provide a comprehensive BTRR proximal proteome, revealing proteins that suppress crossover recombination. We find that RAD54L2, a SNF2-family protein, physically interacts with BLM and suppresses sister chromatid exchanges. RAD54L2 is important for recruitment of BLM to chromatin and requires an intact ATPase domain to promote non-crossover recombination. Thus, the BTRR proximity map identifies a regulator of recombination.

同源重组（Homologous recombination）是一种在所有生命域中保守存在的高保真DNA修复机制，对维持基因组完整性至关重要。同源重组修复相关基因的突变不仅可能成为癌症驱动因素，部分突变还会引发遗传疾病。具体而言，布鲁姆解旋酶（Bloom helicase, BLM）的突变会引发布鲁姆综合征（Bloom Syndrome）——一种罕见的常染色体隐性遗传病，其特征为姐妹染色单体交换（sister chromatid exchanges）频率升高，并易罹患多种癌症。布鲁姆综合征的病理机制源于BLM-TOP3A-RMI1-RMI2复合物（简称BTRR复合物）的活性受损，该复合物可抑制交叉重组（crossover recombination），从而避免潜在有害的基因组重排。本研究提供了一套完整的BTRR邻近蛋白质组数据集，揭示了可抑制交叉重组的蛋白质。研究发现，SNF2家族蛋白RAD54L2可与BLM发生物理相互作用，并抑制姐妹染色单体交换。RAD54L2对于BLM向染色质的招募至关重要，且其需具备完整的ATP酶结构域（ATPase domain）才能促进非交叉重组（non-crossover recombination）。综上，本研究的BTRR邻近定位图谱鉴定出了一种重组调控因子。