LEDGF (p75) promotes DNA-end resection and homologous recombination
LEDGF (p75) promotes DNA-end resection and homologous recombination
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DOI：
10.1038/nsmb.2314
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发表时间：
2012-08-01
影响因子：
16.8
通讯作者：
Jaattela, Marja
中科院分区：
文献类型：
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作者：
Daugaard, Mads;Baude, Annika;Jaattela, Marja
透镜上皮衍生生长因子p75剪接变体（LEDGF）是一种染色质结合蛋白，已知其抗凋亡活性和将人类免疫缺陷病毒引导到活性转录单位的能力。在这里，我们表明，LEDGF促进DNA双链断裂（DSB）的同源重组修复途径的修复。LEDGF的消耗损害了C末端结合蛋白相互作用蛋白（CtIP）到DNA DSB的募集以及随后的CtIP依赖性DNA末端切除。LEDGF通过其Pro-Trp-Trp-Pro（PWWP）结构域与染色质组成性相关，PWWP结构域优先结合活性转录单位的表观遗传甲基赖氨酸组蛋白标志物。LEDGF以DNA损伤依赖性方式结合CtIP，从而增强其对活性染色质的束缚并促进其接近DNA DSB。这些数据突出了PWWP结构域蛋白在DNA修复中的作用，并为LEDGE的抗凋亡和癌细胞存活活性提供了分子解释。
Lens epithelium derived growth factor p75 splice variant (LEDGF) is a chromatin-binding protein known for its antiapoptotic activity and ability to direct human immunodeficiency virus into active transcription units. Here we show that LEDGF promotes the repair of DNA double-strand breaks (DSBs) by the homologous recombination repair pathway. Depletion of LEDGF impairs the recruitment of C-terminal binding protein interacting protein (CtIP) to DNA DSBs and the subsequent CtIP-dependent DNA-end resection. LEDGF is constitutively associated with chromatin through its Pro-Trp-Trp-Pro (PWWP) domain that binds preferentially to epigenetic methyl-lysine histone markers characteristic of active transcription units. LEDGF binds CtIP in a DNA damage dependent manner, thereby enhancing its tethering to the active chromatin and facilitating its access to DNA DSBs. These data highlight the role of PWWP-domain proteins in DNA repair and provide a molecular explanation for the antiapoptotic and cancer cell survival activities of LEDGE.