Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation.
Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation.
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DOI：
10.1016/j.molcel.2022.01.020
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发表时间：
2022-02
期刊：
影响因子：
16
通讯作者：
Chuanchao Zhang;B. Zhou;F. Gu;Hongmei Liu;Honglin Wu;Fuwen Yao;Hui Zheng;Hui Fu;Wei Chong-We
中科院分区：
文献类型：
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作者：
Chuanchao Zhang;B. Zhou;F. Gu;Hongmei Liu;Honglin Wu;Fuwen Yao;Hui Zheng;Hui Fu;Wei Chong-We
通过组合靶向DNA损伤反应（DDR）途径的合成致死性提供了令人兴奋的抗癌治疗益处。目前，长链非编码RNA（lncRNA）与肿瘤耐药性有关，但其在DDR中的潜在意义仍不清楚。在这里，我们报告，人类lncRNA，CTD-2256P15.2，编码一种微肽，命名为PAR-扩增和CtIP-维持微肽（PACMP），具有双重功能，以维持CtIP丰度和促进聚（ADP-核糖基）化。PACMP不仅通过抑制CtIP与KLHL 15的结合来阻止CtIP的泛素化，而且直接与DNA损伤诱导的聚ADP核糖链结合，增强PARP 1依赖的聚ADP核糖基化。单独靶向PACMP通过引起CtIP和PARP抑制之间的合成致死相互作用来抑制肿瘤生长，并赋予对PARP/ATR/CDK 4/6抑制剂、电离辐射、表阿霉素和喜树碱的敏感性。我们的研究结果表明，lncRNA衍生的微肽通过调节DDR来调节癌症进展和耐药性，其抑制可用于增强现有的抗癌治疗策略。
Synthetic lethality through combinatorial targeting DNA damage response (DDR) pathways provides exciting anticancer therapeutic benefit. Currently, the long noncoding RNAs (lncRNAs) have been implicated in tumor drug resistance; however, their potential significance in DDR is still largely unknown. Here, we report that a human lncRNA, CTD-2256P15.2, encodes a micropeptide, named PAR-amplifying and CtIP-maintaining micropeptide (PACMP), with a dual function to maintain CtIP abundance and promote poly(ADP-ribosyl)ation. PACMP not only prevents CtIP from ubiquitination through inhibiting the CtIP-KLHL15 association but also directly binds DNA damage-induced poly(ADP-ribose) chains to enhance PARP1-dependent poly(ADP-ribosyl)ation. Targeting PACMP alone inhibits tumor growth by causing a synthetic lethal interaction between CtIP and PARP inhibitions and confers sensitivity to PARP/ATR/CDK4/6 inhibitors, ionizing radiation, epirubicin, and camptothecin. Our findings reveal that a lncRNA-derived micropeptide regulates cancer progression and drug resistance by modulating DDR, whose inhibition could be employed to augment the existing anticancer therapeutic strategies.