Turning a new page on nucleostemin and self-renewal

Abstract

A quintessential trait of stem cells is embedded in their ability to selfrenew without incurring DNA damage as a result of genome replication. One key self-renewal factor is the nucleolar GTPbinding protein nucleostemin (also known as guanine-nucleotidebinding protein-like 3, GNL3, in invertebrate species). Several studies have recently pointed to an unexpected role of nucleostemin in safeguarding the genome integrity of stem and cancer cells. Since its discovery, the predominant presence of nucleostemin in the nucleolus has led to the notion that it might function in the cardcarrying event of the nucleolus -the biogenesis of ribosomes. As tantalizing as this might be, a ribosomal role of nucleostemin is refuted by evidence from recent studies, which argues that nucleostemin depletion triggers a primary event of DNA damage in S phase cells that then leads to ribosomal perturbation. Furthermore, there have been conflicting reports regarding the p53 dependency of nucleostemin activity and the cell cycle arrest profile of nucleostemindepleted cells. In this Commentary, I propose a model that explains how the many contradictory observations surrounding nucleostemin can be reconciled and suggest that this protein might not be as multitasking as has been previously perceived. The story of nucleostemin highlights the complexity of the underlying molecular events associated with the appearance of any cell biological phenotype and also signifies a new understanding of the genome maintenance program in stem cells.

Cross-Tissue Identification of Somatic Stem and Progenitor Cells Using a Single-Cell RNA-Sequencing Derived Gene Signature

“…E, Supporting Information Fig. S2D) . It is thus possible that some of these misclassification events do not represent false positive predictions, as these multipotent cells may genuinely be very close to ISCs and may thus also be categorized as SSPCs .…”

Coessential Genetic Networks Reveal the Organization and Constituents of a Dynamic Cellular Stress Response

“…Specifically, C16orf72 and HUWE1 depletion independently resulted in underubiquitination of many proteins ( Figure 6J). These included known HUWE1 substrates, such as TP53 (notably, C16orf72's second-ranked fitness anticorrelation; r = -0.32, p = 6e-17), as well as putative HUWE1 substrates suggested from prior high throughput studies, such as GNL3/nucleostemin, a protein which promotes genome integrity during DNA replication (Tsai, 2014). Remarkably, of the 20 proteins which had highly significant changes in ubiquitination after C16orf72 and HUWE1 depletion, only UBE2L3 had increased ubiquitination.…”

Balancing self-renewal against genome preservation in stem cells: How do they manage to have the cake and eat it too?

“…NS has been shown to play indispensable roles in several fundamental biological events, including early and late embryogenesis, adult tissue regeneration, and pluripotency reprogramming [164–170]. We recently discovered its key mechanism of action in protecting proliferating cells from DNA damage during the S phase [168, 169, 171–174], which highlights the importance of genome maintenance in self-renewal and suggests NS as a new regulatory component in the repair of replicative DNA damage [174, 175]. The role of NS in genome protection was first discovered by its ability to reduce telomeric DNA damage [171].…”