Department of Immunology and Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Nucleic Acids Res. 2024 May 8;52(8):4422-4439. doi: 10.1093/nar/gkae204.
Efficient repair of DNA double-strand breaks in the Ig heavy chain gene locus is crucial for B-cell antibody class switch recombination (CSR). The regulatory dynamics of the repair pathway direct CSR preferentially through nonhomologous end joining (NHEJ) over alternative end joining (AEJ). Here, we demonstrate that the histone acetyl reader BRD2 suppresses AEJ and aberrant recombination as well as random genomic sequence capture at the CSR junctions. BRD2 deficiency impairs switch (S) region synapse, optimal DNA damage response (DDR), and increases DNA break end resection. Unlike BRD4, a similar bromodomain protein involved in NHEJ and CSR, BRD2 loss does not elevate RPA phosphorylation and R-loop formation in the S region. As BRD2 stabilizes the cohesion loader protein NIPBL in the S regions, the loss of BRD2 or NIPBL shows comparable deregulation of S-S synapsis, DDR, and DNA repair pathway choice during CSR. This finding extends beyond CSR, as NIPBL and BRD4 have been linked to Cornelia de Lange syndrome, a developmental disorder exhibiting defective NHEJ and Ig isotype switching. The interplay between these proteins sheds light on the intricate mechanisms governing DNA repair and immune system functionality.
高效修复免疫球蛋白重链基因座中的 DNA 双链断裂对 B 细胞抗体类别转换重组（CSR）至关重要。修复途径的调控动态通过非同源末端连接（NHEJ）而非替代末端连接（AEJ）优先指导 CSR。在这里，我们证明组蛋白乙酰基阅读器 BRD2 抑制 AEJ 和异常重组以及 CSR 连接处的随机基因组序列捕获。BRD2 缺陷会损害开关（S）区域突触、最佳 DNA 损伤反应（DDR），并增加 DNA 断裂端切除。与参与 NHEJ 和 CSR 的类似溴结构域蛋白 BRD4 不同，BRD2 的缺失不会增加 S 区域中 RPA 的磷酸化和 R 环形成。由于 BRD2 在 S 区域中稳定黏合加载蛋白 NIPBL，因此 BRD2 或 NIPBL 的缺失会导致 S-S 突触、DDR 和 CSR 期间 DNA 修复途径选择出现类似的失调。这一发现不仅限于 CSR，因为 NIPBL 和 BRD4 与 Cornelia de Lange 综合征有关，Cornelia de Lange 综合征是一种发育障碍，表现为 NHEJ 和 Ig 同种型转换缺陷。这些蛋白质之间的相互作用揭示了调节 DNA 修复和免疫系统功能的复杂机制。
