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.

中文翻译：

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BRD2 与 NIPBL 合作通过促进 DNA 修复来促进抗体类别转换重组

Ig 重链基因座中 DNA 双链断裂的有效修复对于 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优先通过非同源末端连接 (NHEJ) 而非替代末端连接 (AEJ) 来指导 CSR。在这里，我们证明组蛋白乙酰读取器 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 断裂末端切除。与 BRD4（一种参与 NHEJ 和 CSR 的类似溴结构域蛋白）不同，BRD2 缺失不会提高 S 区 RPA 磷酸化和 R 环形成。由于 BRD2 稳定了 S 区域的内聚装载蛋白 NIPBL，因此 BRD2 或 NIPBL 的缺失表明 CSR 期间 SS 突触、DDR 和 DNA 修复途径选择的调节失调。这一发现超出了 CSR 的范畴，因为 NIPBL 和 BRD4 与 Cornelia de Lange 综合征有关，这是一种表现出 NHEJ 和 Ig 同种型转换缺陷的发育障碍。这些蛋白质之间的相互作用揭示了控制 DNA 修复和免疫系统功能的复杂机制。