Cell Cycle

• The cell cycle refers to a series of coordinated events through which a cell replicates its genome and undergoes division to produce daughter cells.
• In most eukaryotes, cell cycle progression is regulated by a highly complex and evolutionary conserved molecular framework.
• External stimuli such as mitogens and growth factors trigger a cell’s entry and commitment to the cell cycle, while internal checkpoints continuously monitor phase fidelity. Once external conditions are met and internal quality checks pass, the cell proceeds through a series of tightly timed, irreversible transitions to produce two daughter cells.
  
• A typical cell cycle in mammalian cells (more precisely called mitotic cell cycle, to distinguish specialised cycles such as meiosis or endoreduplication) is divided into four distinct phases:
  • G₁ (Gap 1) phase
  • S (synthesis) phase 
  • G₂ (Gap 2) phase  
  • M (Mitotic) Phase
• The G1, S, and G2 phases are collectively known as interphase. The purpose of interphase is to synthesize all essential cellular components, including the duplication of the genome, and to prepare the cell for division. The interphase is crucial for ensuring that the cell has all the necessary materials and conditions for successful mitosis.
• G1 (Gap 1) phase: After cytokinesis, a mother cell generates two daughter cells. The G1 phase is the interval between cytokinesis and the S phase, during which cells make the crucial decision to either divide or not. If a cell decides not to divide, it enters a phase called G₀. Conversely, if the decision is to divide, the cell prepares for a new round of division, which involves synthesizing RNA and proteins necessary for DNA replication. In most cells, the G1 phase is the longest part of the cell cycle, with dividing cells typically spending about 60% of their time in this phase.  Additionally, the progression through G1 is monitored by checkpoints, such as the restriction point (R) or the G1/S checkpoint, which ensure the cell is ready for DNA synthesis and division. (Read G1/S Transition)
• S Phase: DNA replication occurs during the S (synthesis) phase of the cell cycle. During this phase, the intra-S-phase checkpoint plays a crucial role in monitoring the progression of DNA replication. This checkpoint ensures that the DNA is accurately replicated and that any damage is repaired before the cell proceeds to the next phase, thereby maintaining genomic integrity.
  
• G2 (Gap 2) phase: New proteins are synthesized during the G2 phase in preparation for mitosis. Progression from the G2 phase to the M phase is monitored by the G2/M checkpoint. This checkpoint ensures that the cell’s DNA has been accurately replicated and that there are no errors or damage before the cell enters mitosis, thereby safeguarding the integrity of the genetic material in the daughter cells.
  
• M-phase: The M phase refers to the division of the nucleus (mitosis or karyokinesis) and the cytoplasm (cytokinesis).
  • Mitosis involves several key processes, including the assembly and disassembly of the nuclear membrane, chromosome condensation, mitotic spindle assembly, and the segregation of sister chromatids.
  • At the end of mitosis, the formation of a cleavage furrow begins between the two daughter nuclei. The completion of the cleavage furrow leads to the physical separation of the cell into two daughter cells during cytokinesis. This coordinated process ensures that each daughter cell receives an identical set of chromosomes and the necessary cellular components to function independently.
• The periodic expression of specific cell cycle genes, called cyclins, forms an important regulatory control that ensures the smooth progression of the cell cycle. Together with their catalytic partners, Cyclin-dependent kinases (CDKs), they drive the progression of the cell cycle through its different phases.
• In addition to cyclins and CDKs, the cell cycle is tightly controlled by Cyclin‑dependent kinase inhibitors (CKIs), which act as negative regulators of CDK activity. CKIs, such as members of the INK4 (e.g., p15, p16) and Cip/Kip (e.g., p21, p27, p57) families, bind directly to CDKs or cyclin–CDK complexes to inhibit their function. 
• Cell cycle-dependent genes can be regulated at several levels:
  • Transcriptional (RNA synthesis rate)
  • Post-transcription (RNA stability and degradation)
  • Translation (Protein synthesis rate)
  • Post-translational level (protein modification e.g., phosphorylation and degradation)
• A complete cell cycle event ultimately results in the formation of two genetically identical daughter cells from a mother cell. Specialized cell cycles, such as endoreduplication, asymmetrical cell division, cell division during development, and stem cell division, have also been documented.
  
• Loss of control over the cell cycle can result in uncontrolled cell proliferation, which may lead to cancer (Vermeulen K., et al., 2003). 

References/Further reading:

• Vermeulen K., et al., 2003. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 36(3), 131-149. DOI: 10.1046/j.1365-2184.2003.00266.x, PMID-12814430, PMCID: PMC6496723 (Download PDF), Wiley (Download PDF), Scopus, Google Scholar 
• Wang, Z. 2021. Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling. Cells. 10 (12), 3327. PMID-34943835, DOI: 10.3390/cells10123327, PMCID: PMC8699227 (Download PDF), MDPI  (Download PDF), Scopus   
• Hartwell L.H., et al., 1974. Genetic control of the cell division cycle in yeast. Science. 183(4120):46-51. DOI: 10.1126/science.183.4120.46 , PMID-4587263, Science