Jinesh Goodwin G, Smallin Marian T, Mtchedlidze Nino, Napoli Marco, Lockhart John H, Flores Elsa R, Brohl Andrew S
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.
iScience. 2024 Oct 10;27(11):111132. doi: 10.1016/j.isci.2024.111132. eCollection 2024 Nov 15.
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.
19号染色体微小RNA簇（C19MC）根据胎盘滋养层细胞的多核状态来限制病毒。然而，C19MC与多核化之间的关系尚不清楚。在此，我们表明C19MC在多个癌症类型亚群中与减数分裂相关基因共表达。我们发现了一种新的减数分裂III，其减数分裂核分裂（MND）和胞质分裂同时进行。C19MC促进减数分裂桥接染色体阻断MND和胞质分裂以产生多核细胞。MND始于核膜内陷形成核（仁）侵袭性细胞质（NiC）、线粒体和蛋白质货物。极光激酶B调节货物从NiC流出，而C19MC、细胞周期蛋白依赖性激酶1（CDK1）和自噬促进货物流入以扩大NiC大小以促进MND进程。利用CRISPR人类基因工程，我们证明了C19MC表达是NiC驱动的MND和多核化所必需的。这一发现对癌症-病原体相互作用、免疫治疗、病毒垂直传播、抗病毒研究和SpCas9-CRISPR治疗学具有重要意义。
