Programmed DNA recombination in mammalian cells occurs predominantly in a directional manner. While random DNA breaks are typically repaired both by deletion and by inversion at approximately equal proportions, V(D)J and class switch recombination (CSR) of immunoglobulin heavy chain gene overwhelmingly delete intervening sequences to yield productive rearrangement. What factors channel chromatin breaks to deletional CSR in lymphocytes is unknown. Integrating CRISPR knockout and chemical perturbation screening we here identify the Snf2-family helicase-like ERCC6L2 as one such factor. We show that ERCC6L2 promotes double-strand break end-joining and facilitates optimal CSR in mice. At the cellular levels, ERCC6L2 rapidly engages in DNA repair through its C-terminal domains. Mechanistically, ERCC6L2 interacts with other end-joining factors and plays a functionally redundant role with the XLF end-joining factor in V(D)J recombination. Strikingly, ERCC6L2 controls orientation-specific joining of broken ends during CSR, which relies on its helicase activity. Thus, ERCC6L2 facilitates programmed recombination through directional repair of distant breaks.

中文翻译：

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ERCC6L2 促进哺乳动物细胞中的 DNA 定向特异性重组。

哺乳动物细胞中的程序性 DNA 重组主要以定向方式发生。虽然随机 DNA 断裂通常通过删除和倒位以大致相等的比例进行修复，但免疫球蛋白重链基因的 V(D)J 和类别转换重组 (CSR) 压倒性地删除干预序列以产生生产性重排。是什么因素将染色质断裂引导到淋巴细胞中的缺失 CSR 尚不清楚。整合 CRISPR 敲除和化学扰动筛选，我们在此将 Snf2 家族解旋酶样 ERCC6L2 确定为此类因素之一。我们表明 ERCC6L2 促进双链断裂末端连接并促进小鼠的最佳 CSR。在细胞水平上，ERCC6L2 通过其 C 端结构域快速参与 DNA 修复。机械地，ERCC6L2 与其他末端连接因子相互作用，并在 V(D)J 重组中与 XLF 末端连接因子一起发挥功能冗余作用。引人注目的是，ERCC6L2 在 CSR 期间控制断端的定向连接，这依赖于其解旋酶活性。因此，ERCC6L2 通过对远处断裂的定向修复来促进程序化重组。