The integrity of cellular genome is continuously challenged by endogenous and exogenous DNA damaging agents. If DNA damage is not removed in a timely fashion the replisome may stall at DNA lesions, causing fork collapse and genetic instability. Base excision DNA repair (BER) is the most important pathway for the removal of oxidized or mono-alkylated DNA. While the main components of the BER pathway are well defined, its regulatory mechanism is not yet understood. We report here that the splicing factor ISY1 enhances apurinic/apyrimidinic endonuclease 1 (APE1) activity, the multifunctional enzyme in BER, by promoting its 5'-3' endonuclease activity. ISY1 expression is induced by oxidative damage, which would provide an immediate up-regulation of APE1 activity in vivo and enhance BER of oxidized bases. We further found that APE1 and ISY1 interact, and ISY1 enhances the ability of APE1 to recognize abasic sites in DNA. Using purified recombinant proteins, we reconstituted BER and demonstrated that ISY1 markedly promoted APE1 activity in both the short- and long-patch BER pathways. Our study identified ISY1 as a regulator of the BER pathway, which would be of physiological relevance where suboptimal levels of APE1 are present. The interaction of ISY1 and APE1 also establishes a connection between DNA damage repair and pre-mRNA splicing.

中文翻译：

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剪接组件ISY1在碱基切除修复中调节APE1。

细胞基因组的完整性不断受到内源性和外源性DNA破坏剂的挑战。如果不能及时消除DNA损伤，那么复制体可能会停滞在DNA损伤处，从而导致叉子塌陷和遗传不稳定。碱基切除DNA修复（BER）是去除氧化或单烷基化DNA的最重要途径。虽然BER通路的主要组成部分已得到很好的定义，但其调控机制尚不清楚。我们在这里报告，剪接因子ISY1通过促进其5'-3'内切核酸酶活性增强了嘌呤/嘧啶内切核酸酶1（APE1）的活性，BER中的多功能酶。ISY1表达是由氧化损伤诱导的，该氧化损伤将提供体内APE1活性的即时上调并增强氧化碱基的BER。我们进一步发现APE1和ISY1相互作用，而ISY1增强了APE1识别DNA中脱碱基位点的能力。使用纯化的重组蛋白，我们重建了BER，并证明了ISY1在短和长补丁BER途径中均显着提高了APE1的活性。我们的研究确定ISY1是BER通路的调节剂，在存在亚最佳水平的APE1的情况下，它具有生理相关性。ISY1和APE1的相互作用还建立了DNA损伤修复和mRNA剪接前的联系。如果存在亚最佳水平的APE1，这将具有生理相关性。ISY1和APE1的相互作用还建立了DNA损伤修复和mRNA剪接前的联系。如果存在亚最佳水平的APE1，这将具有生理相关性。ISY1和APE1的相互作用还建立了DNA损伤修复和mRNA剪接前的联系。