Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Department of General Virology, Martinistrasse 52, 20251 Hamburg, Germany.
Nucleic Acids Res. 2012 Dec;40(22):11363-79. doi: 10.1093/nar/gks868. Epub 2012 Oct 2.
Survival time-associated plant homeodomain (PHD) finger protein in Ovarian Cancer 1 (SPOC1, also known as PHF13) is known to modulate chromatin structure and is essential for testicular stem-cell differentiation. Here we show that SPOC1 is recruited to DNA double-strand breaks (DSBs) in an ATM-dependent manner. Moreover, SPOC1 localizes at endogenous repair foci, including OPT domains and accumulates at large DSB repair foci characteristic for delayed repair at heterochromatic sites. SPOC1 depletion enhances the kinetics of ionizing radiation-induced foci (IRIF) formation after γ-irradiation (γ-IR), non-homologous end-joining (NHEJ) repair activity, and cellular radioresistance, but impairs homologous recombination (HR) repair. Conversely, SPOC1 overexpression delays IRIF formation and γH2AX expansion, reduces NHEJ repair activity and enhances cellular radiosensitivity. SPOC1 mediates dose-dependent changes in chromatin association of DNA compaction factors KAP-1, HP1-α and H3K9 methyltransferases (KMT) GLP, G9A and SETDB1. In addition, SPOC1 interacts with KAP-1 and H3K9 KMTs, inhibits KAP-1 phosphorylation and enhances H3K9 trimethylation. These findings provide the first evidence for a function of SPOC1 in DNA damage response (DDR) and repair. SPOC1 acts as a modulator of repair kinetics and choice of pathways. This involves its dose-dependent effects on DNA damage sensors, repair mediators and key regulators of chromatin structure.
卵巢癌 1 相关生存时间的植物同源结构域（PHD）手指蛋白（SPOC1，也称为 PHF13）已知可调节染色质结构，是睾丸干细胞分化所必需的。在这里，我们表明 SPOC1 以 ATM 依赖性方式被募集到 DNA 双链断裂（DSB）。此外，SPOC1 定位于内源性修复焦点，包括 OPT 结构域，并在大的 DSB 修复焦点处积累，这些焦点是异染色质位点延迟修复的特征。SPOC1 的耗竭增强了 γ 辐照（γ-IR）后电离辐射诱导焦点（IRIF）形成、非同源末端连接（NHEJ）修复活性和细胞放射抗性的动力学，但损害同源重组（HR）修复。相反，SPOC1 的过表达延迟了 IRIF 的形成和 γH2AX 的扩展，降低了 NHEJ 修复活性并增强了细胞放射敏感性。SPOC1 介导了 DNA 压缩因子 KAP-1、HP1-α 和 H3K9 甲基转移酶（KMT）GLP、G9A 和 SETDB1 的染色质关联的剂量依赖性变化。此外，SPOC1 与 KAP-1 和 H3K9 KMT 相互作用，抑制 KAP-1 磷酸化并增强 H3K9 三甲基化。这些发现为 SPOC1 在 DNA 损伤反应（DDR）和修复中的功能提供了第一个证据。SPOC1 作为修复动力学和途径选择的调节剂。这涉及到它对 DNA 损伤传感器、修复介质和染色质结构的关键调节剂的剂量依赖性影响。
