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

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. [Display omitted] •lncRNA CTD-2256P15.2 encodes a micropeptide PACMP•PACMP prevents CtIP from KLHL15-mediated ubiquitination and proteasomal degradation•PACMP acts as an activator to promote PARP1-dependent PARylation•PACMP depletion inhibits tumor growth and re-sensitizes tumor cells to PARPi Zhang et al. demonstrate that lncRNA CTD-2256P15.2-encoded PACMP has a dual function in maintaining CtIP protein stability and promoting PARylation signaling in DNA repair. The lncRNA depletion inhibits tumor growth and confers sensitivity to PARP/ATR/CDK4/6 inhibitors and multiple DNA damage-inducing reagents.