Cell Cycle

The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists.

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Definitions

  • Chromatin: the combination of nucleic acids and proteins that makes up chromosomes
  • Histones:
    • Most common protein in chromatin
    • Organize DNA, allowing it to be more tightly or loosely wound
  • Chromosomes:
    • DNA and protein-containing subunits in which genes are organized
    • Usually string-like and diffuse, during mitosis condense into discrete rod-like structures
  • Sister chromatid: 1 of 2 identical halves of a replicated chromosome
  • Centrioles: cylindrical organelles that function as 1 of the attachment poles of the mitotic spindle in a replicating cell (the other end being a kinetochore)
  • Centrosomes: organelle containing centrioles
  • Kinetochore: protein structure that attaches to the central zone of a chromosome (centromere) to which 1 of the ends of the mitotic spindle attaches in a replicating cell (the other end being the centrioles)
  • Centromeres: the region of the chromosome to which the microtubules of the mitotic spindle attach via the kinetochore
  • Mitotic spindle: the microtubule structure created from the disassembled cytoskeleton of a cell along which chromosomes are pulled when they are separated during mitosis

Overview

The cell cycle describes the cyclic sequence of events through which a eukaryotic, proliferating parent cell splits into 2 identical daughter cells.

G0

  • Mature, differentiated cells outside the cell cycle are in this reversible, resting state.
  • Low concentration of growth factor and high population density keep cells in G0.
  • Normal metabolism occurs, but there is no cell division.
  • Specific triggers, such as growth factors, induce some cells to return to G1.

Interphase

G1, S, and G2 phases are grouped together as interphase.

  • G1 (gap 1): duration = approximately 12 hours
    • Occurs immediately after mitosis (cell is half its normal size)
    • Period of cell-volume growth 
    • RNA and protein synthesis take place.
    • Proteins and cellular constituents required for mitosis (e.g., microtubules) are created.
  • S (synthesis): duration = 8–12 hours
    • Chromosomes double, creating identical pairs of sister chromatids (diploid → tetraploid set)
    • Quality assurance phase:
      • Ensures the accuracy of replication
      • DNA mismatch repair occurs
    • Machinery for mitosis is prepared:
      • Centrosomes duplicate
      • Centriole separate
      • Histones synthesized
  • G2 (gap 2): duration = 1.5–3 hours
    • Replication of certain organelles
    • Preparation of structures used to move chromosomes (cytoskeleton is dismantled)
    • Specific proteins that are required for cell division (e.g., RNA molecules) are synthesized.
    • Replication is checked using repair mechanisms.
    • The cell completes the interphase and is ready for mitosis.
5 phases of the cell cycle

The cell cycle, divided into 5 phases

Image by Lecturio.

Cell Division (Mitosis)

During mitosis, the cell’s duplicated DNA is separated and distributed to 2 identical daughter cells. The process lasts approximately 1 hour.

  • Prophase:
    • Chromosomes condense, becoming visible.
    • Microtubules assemble, creating the mitotic spindle attached to the centrioles.
    • Centrosomes migrate toward opposite poles of the cell.
    • Nucleolus is no longer visible. 
    • Nuclear envelope begins to dissolve.
  • Prometaphase:
    • Kinetochores assemble at the chromosome centromeres.
    • Free ends of microtubules connect to the kinetochores.
    • Centrosomes reach the opposite poles.
  • Metaphase:
    • Chromosomes are aligned along the equatorial region (metaphase plate) of the cell. 
    • Each sister chromatid is attached to a mitotic spindle originating from opposite poles.
    • The nuclear envelope completely dissolves.
  • Anaphase: 
    • Kinetochores break down.
    • Sister chromatids become single chromatids or chromosomes.
    • Chromatids migrate to opposite poles along the mitotic spindle. 
    • Spindle fibers opposite the chromatids elongate, stretching the cell into an oval.
  • Telophase:
    • New nuclear envelopes form around the decondensing chromosomes.
    • The spindle apparatus dissolves. 
    • “Cleavage furrow” splits the cell in 2 (cytokinesis)
    • Each of the daughter cells develops a complete cell membrane.
    • Both daughter cells are completely separated from each other.
Mitosis Step by Step

Depiction of stages of mitosis (prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis): Bottom right corner pictures stained cells in the same phase of mitosis taken by fluorescence microscopy.

Image by Lecturio.

Regulation of the Cell Cycle

The cell cycle is tightly regulated. Not passing a checkpoint should trigger programmed cell death (apoptosis). Apoptosis failure results in mutation accumulation, leading to disease.

The cell cycle begins when the cell has:

  • A sufficient minimum size
  • Appropriate nutritional conditions
  • Been stimulated by growth factors, in addition to the absence of anti-mitogenic signals

Molecules regulating the cell cycle

  • Positive regulators: Presence at appropriate concentrations permits the cell cycle to progress.
    • Cyclins:
      • Regulatory proteins released in response to internal and external stimuli at specific stages of the cell cycle.
      • 4 different cyclin concentrations fluctuate predictably during the cycle.
    • Cyclin-dependent kinases (CDK) are protein kinases that are:
      • Activated by cyclins and protein kinases (via phosphorylation)
      • Inhibited by protein phosphatases (via dephosphorylation) and cyclin-dependent kinase inhibitors (CKIs)
    • Nuclear localization sequence (NLS) allows cyclins to enter the cell nucleus as a heterodimer with CDKs.
  • Negative regulators: Activation of these factors blocks the cell cycle. 
    • p53 and p21: halt cell cycle if DNA damage is detected
    • Retinoblastoma protein: halts the G1/S transition
    • If hyperphosphorylation occurs due to cyclin-D/CDK 4/6 dimers → transcription of cyclin E and other proteins for progression to S phase begins.

Restriction points

  • Later G1 phase (G1S checkpoint): irreversible 
    • Regulated by CDK2 and cyclin E
    • Transition between the G1 and S phases determines cell progression to cell division or dormancy in G0 phase.
  • End of the G2 phase (G2M checkpoint)
    • Regulated by CDK1 and cyclin B
    • Checkpoint for favorable environmental conditions and correct and complete replication of DNA 
      • Incomplete genome at this stage will result in cell death.
      • M-phase promoting factors (MPF), which are cyclin-CDK heterodimers, play an important role in this checkpoint.
  • During metaphase (spindle checkpoint): irreversible
    • Ensures that all chromosomes adhere to the spindle microtubules prior to separation in anaphase
    • Tension on the spindle fibers → production of anaphase-promoting complex (APC) 
    • APCs promote breakdown of connexin (kinetochore) proteins between sister chromatids.
  • G1 and G2 phases have further DNA damage checkpoints.
    • The cell cycle can be arrested until damage has been repaired.
    • If the DNA is irreparable, apoptosis is triggered.

References

  1. Clark, M. A. et al. (2018). Biology 2e. https://openstax.org/details/books/biology-2e?Book%20details
  2. Goljan, E. F. (2013). Rapid review pathology: with student consult online access. Elsevier Health Sciences.

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