2. Academic Validation
  3. 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

  • Mol Cell. 2022 Apr 7;82(7):1297-1312.e8. doi: 10.1016/j.molcel.2022.01.020.
Chuanchao Zhang 1,  Bo Zhou 2,  Feng Gu 3,  Hongmei Liu 4,  Honglin Wu 5,  Fuwen Yao 1,  Hui Zheng 1,  Hui Fu 1,  Wei Chong 3,  Shurui Cai 6,  Min Huang 1,  Xiaolu Ma 1,  Zhifang Guo 3,  Tingting Li 4,  Wenyuan Deng 1,  Meiwen Zheng 1,  Qiao Ji 1,  Yongliang Zhao 1,  Yongjie Ma 3,  Qi-En Wang 6,  Tie-Shan Tang 7,  Caixia Guo 8
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing 100101, China.
  • 2 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing 100101, China. Electronic address: zhoub@big.ac.cn.
  • 3 Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
  • 4 State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing 100101, China; State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
  • 6 Department of Radiation Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43016, USA.
  • 7 State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: tangtsh@ioz.ac.cn.
  • 8 CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing 100101, China. Electronic address: guocx@big.ac.cn.
PMID: 35219381 DOI: 10.1016/j.molcel.2022.01.020
Abstract

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.

Keywords

CtIP; DNA damage response; DNA double-strand break repair; PARP inhibitor; drug resistance; long noncoding RNA; micropeptide; poly(ADP-ribosyl)ation; synthetic lethal.

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