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. Epub 2022 Feb 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Repair
  • Endodeoxyribonucleases* / metabolism
  • Humans
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Neoplasms* / genetics
  • Neoplasms* / metabolism
  • Peptides* / pharmacology
  • Poly ADP Ribosylation*
  • Poly Adenosine Diphosphate Ribose / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism


  • KLHL15 protein, human
  • Microfilament Proteins
  • Peptides
  • Poly(ADP-ribose) Polymerase Inhibitors
  • RNA, Long Noncoding
  • Poly Adenosine Diphosphate Ribose
  • Poly(ADP-ribose) Polymerases
  • Endodeoxyribonucleases
  • RBBP8 protein, human