Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation.

Molecular cell 2022 Apr 07

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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. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Chuanchao Zhang, Bo Zhou, Feng Gu, Hongmei Liu, Honglin Wu, Fuwen Yao, Hui Zheng, Hui Fu, Wei Chong, Shurui Cai, Min Huang, Xiaolu Ma, Zhifang Guo, Tingting Li, Wenyuan Deng, Meiwen Zheng, Qiao Ji, Yongliang Zhao, Yongjie Ma, Qi-En Wang, Tie-Shan Tang, Caixia Guo. Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation. Molecular cell. 2022 Apr 07;82(7):1297-1312.e8