PAXX is a recently identified component of the nonhomologous end joining (NHEJ) DNA repair pathway. The molecular mechanisms of PAXX action remain largely unclear. Here we characterise the interactomes of PAXX and its paralogs, XLF and XRCC4, to show that these factors share the ability to interact with DNA polymerase λ (Pol λ), stimulate its activity and are required for recruitment of Pol λ to laser-induced DNA damage sites. Stimulation of Pol λ activity by XRCC4 paralogs requires a direct interaction between the SP/8 kDa domain of Pol λ and their N-terminal head domains to facilitate recognition of the 5' end of substrate gaps. Furthermore, PAXX and XLF collaborate with Pol λ to promote joining of incompatible DNA ends and are redundant in supporting Pol λ function in vivo. Our findings identify Pol λ as a novel downstream effector of PAXX function and show XRCC4 paralogs act in synergy to regulate polymerase activity in NHEJ.

中文翻译：

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PAXX 及其旁系同源物协同指导 DNA 聚合酶 λ 在 DNA 修复中的活性。

PAXX 是最近发现的非同源末端连接 (NHEJ) DNA 修复途径的组成部分。PAXX 作用的分子机制在很大程度上仍不清楚。在这里，我们描述了 PAXX 及其旁系同源物 XLF 和 XRCC4 的相互作用组，以表明这些因子具有与 DNA 聚合酶 λ (Pol λ) 相互作用的能力，刺激其活性，并且是 Pol λ 募集到激光诱导的 DNA 所必需的损坏部位。XRCC4 paralogs 对 Pol λ 活性的刺激需要 Pol λ 的 SP/8 kDa 结构域与其 N 端头部结构域之间的直接相互作用，以促进识别底物间隙的 5' 端。此外，PAXX 和 XLF 与 Pol λ 合作以促进不相容的 DNA 末端的连接，并且在体内支持 Pol λ 功能方面是多余的。