SLFN11 inhibits checkpoint maintenance and homologous recombination repair
SLFN11 inhibits checkpoint maintenance and homologous recombination repair
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DOI：
10.15252/embr.201540964
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发表时间：
2016-01-01
期刊：
影响因子：
7.7
通讯作者：
Huang, Jun
中科院分区：
文献类型：
--
作者：
Mu, Yanhua;Lou, Jiangman;Huang, Jun
SLFN 11的高表达水平与人类癌细胞对DNA损伤剂的敏感性相关。然而，人们对潜在的机制知之甚少。在这里，我们表明SLFN 11直接与RPA 1相互作用，并以RPA 1依赖的方式被招募到DNA损伤位点。此外，我们确定SLFN 11通过促进RPA-ssDNA复合物的不稳定来抑制检查点维持和同源重组修复，从而使表达高内源性SLFN 11水平的癌细胞系对DNA损伤剂敏感。最后，我们证明了SLFN 11的RPA 1结合能力是其在DNA损伤反应中的功能所必需的。我们的研究结果不仅为高水平表达SLFN 11的癌细胞系的药物敏感性的分子机制提供了新的见解，而且还表明SLFN 11表达可以作为生物标志物来预测对DNA损伤治疗剂的反应。
High expression levels of SLFN11 correlate with the sensitivity of human cancer cells to DNA-damaging agents. However, little is known about the underlying mechanism. Here, we show that SLFN11 interacts directly with RPA1 and is recruited to sites of DNA damage in an RPA1-dependent manner. Furthermore, we establish that SLFN11 inhibits checkpoint maintenance and homologous recombination repair by promoting the destabilization of the RPA-ssDNA complex, thereby sensitizing cancer cell lines expressing high endogenous levels of SLFN11 to DNA-damaging agents. Finally, we demonstrate that the RPA1-binding ability of SLFN11 is required for its function in the DNA damage response. Our findings not only provide novel insight into the molecular mechanisms underlying the drug sensitivity of cancer cell lines expressing SLFN11 at high levels, but also suggest that SLFN11 expression can serve as a biomarker to predict responses to DNA-damaging therapeutic agents.