C19MC drives nucleolar invasion of mitochondria and meiotic nuclear division in human cancers
Goodwin G. Jinesh,
Marian T. Smallin,
Nino Mtchedlidze,
Marco Napoli,
John H. Lockhart,
Elsa R. Flores,
Andrew S. Brohl
Affiliations
Goodwin G. Jinesh
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Corresponding author
Marian T. Smallin
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Nino Mtchedlidze
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Marco Napoli
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
John H. Lockhart
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Elsa R. Flores
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
Andrew S. Brohl
Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Sarcoma Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Corresponding author
Summary: The chromosome-19 miRNA cluster (C19MC) restricts viruses depending on the multinucleated state of placental trophoblasts. However, the relationship of C19MC to multinucleation is unknown. Here we show that C19MC is coexpressed in multiple cancer type subsets with meiosis-related genes. We discovered a novel meiosis-III that exhibits simultaneous progression of meiotic nuclear division (MND) and cytokinesis. C19MC promotes meiotic bridged-chromosomes to block MND and cytokinesis to generate multinucleated cells. MND starts with the invagination of nuclear membrane to form nucle(ol)ar invasive cytoplasm (NiC), mitochondria and protein cargoes. Aurora-B regulates the efflux of cargos from NiC, whereas C19MC, CDK1, and autophagy promote cargo influx to inflate NiC size for MND progression. Using CRISPR human genetic engineering we demonstrate that the C19MC expression is required for NiC-driven MND and multinucleation. This discovery has impacts on cancer-pathogen interactions, immunotherapy, vertical transmission of viruses, antiviral research and SpCas9-CRISPR therapeutics.
