title: Knockout of Drosophila RNase ZL impairs mitochondrial transcript processing, respiration and cell cycle progression.
abstract: RNase Z(L) is a highly conserved tRNA 3'-end processing endoribonuclease. Similar to its mammalian counterpart, Drosophila RNase Z(L) (dRNaseZ) has a mitochondria targeting signal (MTS) flanked by two methionines at the N-terminus. Alternative translation initiation yields two protein forms: the long one is mitochondrial, and the short one may localize in the nucleus or cytosol. Here, we have generated a mitochondria specific knockout of the dRNaseZ gene. In this in vivo model, cells deprived of dRNaseZ activity display impaired mitochondrial polycistronic transcript processing, increased reactive oxygen species (ROS) and a switch to aerobic glycolysis compensating for cellular ATP. Damaged mitochondria impose a cell cycle delay at the G2 phase disrupting cell proliferation without affecting cell viability. Antioxidants attenuate genotoxic stress and rescue cell proliferation, implying a critical role for ROS. We suggest that under a low-stress condition, ROS activate tumor suppressor p53, which modulates cell cycle progression and promotes cell survival. Transcriptional profiling of p53 targets confirms upregulation of antioxidant and cycB-Cdk1 inhibitor genes without induction of apoptotic genes. This study implicates Drosophila RNase Z(L) in a novel retrograde signaling pathway initiated by the damage in mitochondria and manifested in a cell cycle delay before the mitotic entry.
authors.affiliation: Department of Biology, Fordham University, Bronx, NY 10458, USA.
authors.forename: Xie
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Biology, Fordham University, Bronx, NY 10458, USA Center for Cancer, Genetic Diseases, and Gene Regulation, Fordham University, Bronx, NY 10458, USA dubrovsky@fordham.edu.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Dubrovsky
mesh_terms: D000818:Animals; D002453:Cell Cycle; D004249:DNA Damage; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D055786:Gene Knockout Techniques; D006019:Glycolysis; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D018384:Oxidative Stress; D021382:Protein Sorting Signals; D012323:RNA Processing, Post-Transcriptional; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D021382:Protein Sorting Signals; D017382:Reactive Oxygen Species; D004722:Endoribonucleases; C558385:RNaseZ protein, Drosophila