PHF11 promotes DSB resection, ATR signaling, and HR.
PHF11 promotes DSB resection, ATR signaling, and HR.
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DOI：
10.1101/gad.291807.116
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发表时间：
2017-01-01
影响因子：
10.5
通讯作者：
de Lange T
中科院分区：
文献类型：
--
作者：
Gong Y;Handa N;Kowalczykowski SC;de Lange T
在这里，de Lange及其同事报告说，PHF11（植物同源结构域指11）编码一种以前未知的DNA损伤反应因子，参与5′端切除，ATR信号传导和同源重组。生物化学实验表明，PHF 11通过克服RPA对EXO 1的抑制作用来刺激EXO 1，这表明PHF 11（部分）通过促进RPA结合的DNA损伤位点的5′端切除来发挥作用。双链断裂（DSB）的切除在其检测和适当修复中起着关键作用。通过切除形成的3′ ssDNA突起激活ATR依赖性DNA损伤反应（DDR），并且是通过同源重组（HR）进行DSB修复所必需的。PHF11（planthomeodomainfinger11）编码一个未知的DDR因子，参与5′端切除、ATR信号传导和HR。PHF11的缺失减少了对端粒功能障碍和全基因组DNA损伤的ATR信号传导反应，减少了DNA损伤位点的末端切除，导致HR受损和S期DSB的误连接，并增加了对DNA损伤剂的敏感性。PHF 11与ssDNA结合蛋白RPA相互作用，并与包括5′ dsDNA外切核酸酶EXO 1在内的几种核酸酶形成复合物。生物化学实验表明，PHF 11通过克服RPA对EXO 1的抑制作用来刺激EXO 1，这表明PHF 11（部分）通过促进RPA结合的DNA损伤位点的5′端切除来发挥作用。这些发现揭示了PHF11在DSB切除、DNA损伤信号传导和DSB修复中的作用。
Here, de Lange and colleagues report that PHF11 (plant homeodomain finger 11) encodes a previously unknown DNA damage response factor involved in 5′ end resection, ATR signaling, and homologous recombination. Biochemical experiments demonstrated that PHF11 stimulates EXO1 by overcoming its inhibition by RPA, suggesting that PHF11 acts (in part) by promoting 5′ end resection at RPA-bound sites of DNA damage. Resection of double-strand breaks (DSBs) plays a critical role in their detection and appropriate repair. The 3′ ssDNA protrusion formed through resection activates the ATR-dependent DNA damage response (DDR) and is required for DSB repair by homologous recombination (HR). Here we report that PHF11 (plant homeodomain finger 11) encodes a previously unknown DDR factor involved in 5′ end resection, ATR signaling, and HR. PHF11 was identified based on its association with deprotected telomeres and localized to sites of DNA damage in S phase. Depletion of PHF11 diminished the ATR signaling response to telomere dysfunction and genome-wide DNA damage, reduced end resection at sites of DNA damage, resulted in compromised HR and misrejoining of S-phase DSBs, and increased the sensitivity to DNA-damaging agents. PHF11 interacted with the ssDNA-binding protein RPA and was found in a complex with several nucleases, including the 5′ dsDNA exonuclease EXO1. Biochemical experiments demonstrated that PHF11 stimulates EXO1 by overcoming its inhibition by RPA, suggesting that PHF11 acts (in part) by promoting 5′ end resection at RPA-bound sites of DNA damage. These findings reveal a role for PHF11 in DSB resection, DNA damage signaling, and DSB repair.