Cell Cycle G0 Phase and Cell Division Interphase Overview

G0 Phase Definition: A cellular state outside of the replicative cell cycle. furthermore, Classically, cells were thought to enter G0 primarily due to environmental factors, such as nutrient deprivation, which limited the resources necessary for proliferation. therefore, it was thought of as a resting phase. Thus, G0 is now known to take different forms and occur for multiple reasons. For example, most adult neuronal cells, among the most metabolically active cells in the body, which are fully differentiated and reside in a terminal G0 phase. therefore, Neurons reside in this state, not because of limited nutrient supply or stochastic but as a part of their internal genetic programming.

What Type of Cell Enters The G0 Phase?

The G0 phase (G zero phase) or resting phase is a period in the cell cycle in which cells exist during a quiescent state. thus, the G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor getting ready to divide or a distinct quiescent stage that happens outside of the cell cycle.

Some types of cells, like nerve and heart muscle cells, become quiescent once they reach maturity (i.e., when they are terminally differentiated) but continue to perform their main functions for the rest of the organism’s life. Therefore, Multinucleated muscle cells that don’t undergo cytokinesis are also often considered to be in the G0 stage. thus, on occasion, a distinction in terms is created between a G0 cell and a ‘quiescent’ cell (for examples like neurons and heart muscle cells), they will never enter the G1 phase, whereas other G0 cells may.

Cells enter the G0 phase from a cell cycle checkpoint in the G1 phase, like the restriction point (animal cells) or the beginning point (yeast). This sometimes occurs in response to a lack of growth factors or nutrients. therefore, throughout the G0 phase, cell cycle machinery is dismantled and cyclins, cyclin-dependent kinases disappear. thus, Cells then stay remain within the G0 phase until there is a reason for them to divide.

Some cell types in mature organisms, such as parenchymal cells of the liver and kidney, enter the G0 phase semi-permanently and may be induced to begin dividing again only under very specific circumstances. Other types of cells, like epithelial cells, continue to divide throughout an organism’s life and rarely enter G0.

Although several cells within the G0 phase may die along with the organism, not all cells that enter the G0 phase are destined to die; simply a consequence of the cells lacking any stimulation to re-enter in the cell cycle.

Furthermore, Cellular senescence is distinct from quiescence as a result, it is a state that happens in response to DNA damage or degradation that would make a cell’s progeny nonviable. Senescence then, not like quiescence, is usually a biochemical alternative to the self-destruction of such a broken (damaged) cell by apoptosis. Therefore, quiescence is reversible whereas senescence is not.

G0 Phase of Cell Cycle

Cell Cycle G0 Phase: G0 was first recommended as a cell state based on early cell cycle studies. When the first studies defined the four phases of the cell cycle using radioactive labeling techniques, it had been discovered that not all cells in a population proliferate at similar rates. Therefore, a population’s “growth fraction” or the fraction of the population that was growing – was actively proliferating, but other cells existed in a non-proliferative state. furthermore, Some of these nonproliferating cells may respond to extrinsic stimuli and proliferate by re-entering the cell cycle. thus, early contrasting views either considered non-proliferating cells to simply be in an extended G1 phase or in a cell cycle phase distinct from G1 – termed G0( g zero phase). Subsequent research pointed to a restriction point in G1 where cells can enter G0( G0 cell Phase) before the R-point but are committed to mitosis after the R-point. furthermore, These early studies provided evidence for the existence of a G0 stage to which access is restricted. Therefore, these cells do not divide further exit the G1 phase to enter an inactive stage called the quiescent stage.

Cell Cycle: What happens during G0 Phase

The cell cycle is typically divided into the following phases:
G0 phase: Gap section or resting state. Many cells spend most of their time during this phase either at rest or performing assigned duties. Generally resistant to chemotherapy.
G1 phase: Interphase or gap one(1) phase. Cells synthesize DNA and they prepare for cell division.
S phase: synthesis phase. therefore, cells duplicate DNA to create daughter cells.
G2 phase: gap two(2) phase. DNA synthesis completed. Microtubules of mitotic spindles produced.
M phase: mitosis. Division of cellular proteins and DNA into two(2) daughter cells. Return to the G0 or resting phase.

Diversification of G0 states

Three G0 states exist and can be classified as either quiescent (reversible) or irreversible (senescent and differentiated). each of those 3 three states can be entered from the G1 (one) phase before the cell commits to the next round of the cell cycle. Therefore, Quiescence refers to a reversible G0 state where subpopulations of cells reside in a ‘quiescent’ state before entering the cell cycle after activation in response to extrinsic signals.

Furthermore, The quiescent cells are often identified by low RNA content, lack of cell proliferation markers, and increased label retention indicating low cell turnover. Therefore, the senescence is distinct from quiescence because senescence is an irreversible state that cells enter in response to degradation or DNA damage that would make a cell’s progeny nonviable. Such DNA damage can occur from telomere shortening over several cell divisions similarly as reactive oxygen species exposure, oncogene activation, and cell-cell fusion.

Therefore, While senescent cells can no longer replicate, they remain able to perform many normal cellular functions. Thus, senescence is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis. In distinction to cellular senescence, quiescence isn’t a reactive event but a part of the core programming of many different cell types. Finally, differentiated cells are stem cells because have progressed through a differentiation program to reach a mature – terminally differentiated state.
Thus, The differentiated cells continue to stay in G0 and perform their main functions indefinitely.

Features of quiescent stem cells

Epigenetic

Many quiescent stem cells, significantly adult stem cells, additionally share similar epigenetic patterns. For example, H3K27me3 and H3K4me3 are two major histone methylation patterns that form a bivalent domain and are located near transcription initiation sites. Therefore, these epigenetic markers are found to regulate lineage decisions in embryonic stem cells moreover as control quiescence in the hair follicle and muscle stem cells via chromatin modification.

Transcriptomes

The transcriptomes of several types of quiescent stem cells, such as hematopoietic, muscle, and hair follicle, have been characterized through high-throughput techniques, such as microarray and RNA sequencing. Although variations exist in their individual transcriptomes, most quiescent tissue stem cells share a common pattern of gene expression that involves downregulation of cell cycle progression genes, such as cyclin A2, cyclin B1, cyclin E2, and survivin, and upregulation of genes involved in the regulation of transcription and stem cell fate, such as FOXO3 and EZH1. Downregulation of mitochondrial cytochrome C also reflects the low metabolic state of quiescent stem cells.

Regulation of Quiescence

1. Post-Transcriptional Regulation

Post-transcriptional regulation of gene expression via miRNA synthesis has been shown to play an equally important role in the maintenance of stem cell quiescence. miRNA strands bind to the 3’ untranslated region (3’ UTR) of target mRNA’s, preventing their translation into functional proteins. The length of the 3’ UTR of a gene determines its ability to bind to miRNA strands, thereby allowing regulation of quiescence. Some examples of miRNAs in stem cells include miR-126, which controls the PI3K/AKT/mTOR pathway in hematopoietic stem cells, miR-489, which suppresses the DEK oncogene in muscle stem cells, and miR-31, which regulates Myf5 in muscle stem cells. miRNA sequestration of mRNA within ribonucleoprotein complexes allows quiescent cells to store the mRNA necessary for quick entry into the G1 phase

2. Cell Cycle Regulators

Functional tumor suppressor genes, particularly the Rb gene and p53, are required to maintain stem cell quiescence and prevent exhaustion of the progenitor cell pool through excessive divisions. For example, the deletion of all three(3) components of the Rb family of proteins has been shown to halt quiescence in hematopoietic stem cells. Lack of p53 has been shown to prevent the differentiation of these stem cells due to the cells’ inability to exit the cell cycle into the G0 phase. In addition to p53 and Rb, cyclin-dependent kinase inhibitors (CKIs), like p21, p27, and p57, are also important for maintaining quiescence. In mouse hematopoietic stem cells, knockout of p57 and p27 leads to G0 exit through the nuclear import of cyclin D1 and subsequent phosphorylation of Rb. Finally, the Notch signaling pathway has been shown to play an important role in the maintenance of quiescence

3. Response to stress

Stem cells that have been quiescent for a long time often face various environmental stressors, like oxidative stress. therefore, several mechanisms allow these cells to respond to such stressors. the FOXO transcription factors respond to the presence of the reactive oxygen species while LKB1 and HIF1A respond to hypoxic conditions. furthermore, in hematopoietic stem cells, autophagy is induced to respond to metabolic stress.