circPCMTD1: A protein-coding circular RNA that regulates DNA damage response inBCR/ABL-positive leukemias

Abstract

AbstractCircular RNAs are a novel class of RNA transcripts, which regulate important cellular functions in health and disease. Herein, we report on the functional relevance of thecircPCMTD1transcript in acute leukemias. In screening experiments, we found thatcircPCMTD1depletion strongly inhibited the proliferative capacity of leukemic cells withBCR-ABLtranslocations. Mass cytometry experiments identified the aberrant activation of the DNA damage response as an early downstream event ofcircPCMTD1depletion. Inin vivoexperiments,circPCMTD1targeting prolonged the survival of mice engrafted with leukemic blasts harboring the Philadelphia chromosome. Mechanistically, we found thatcircPCMTD1was enriched in the cytoplasm and associated with the ribosomes of the leukemic cells. We detected a cryptic open reading frame within thecircPCMTD1sequence and found thatcircPCMTD1could generate a peptide product. ThecircPCMTD1-derived peptide interacted with proteins of the BTR complex and enhanced BTR complex formation, thereby increasing tolerance to genotoxic stress.