12.1 Phases of the cell cycle and their regulation

The cell cycle is a carefully orchestrated process that ensures proper cell division. It's divided into distinct phases, each with specific events and checkpoints. Understanding these phases is crucial for grasping how cells grow, replicate DNA, and divide.

Regulation of the cell cycle involves cyclins, cyclin-dependent kinases, and checkpoints. These mechanisms work together to control cell division, maintain genomic stability, and prevent uncontrolled growth that could lead to cancer.

Cell Cycle Phases and Regulation

Phases of the cell cycle

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• Interphase
  • G1 phase
    • Cell increases in size and synthesizes proteins and organelles in preparation for DNA replication (ribosomes, mitochondria)
    • Responds to growth factors and nutrients to determine if conditions are suitable for cell division
  • S phase
    • DNA replication occurs resulting in the duplication of the cell's genetic material
    • Each chromosome is replicated to form two identical sister chromatids connected by a centromere
  • G2 phase
    • Cell continues to grow and synthesize proteins in preparation for mitosis
    • Organelles and cellular components are duplicated (Golgi apparatus, endoplasmic reticulum)
    • DNA repair mechanisms check for and fix any errors that occurred during replication
• Mitosis (M phase)
  • Prophase
    • Chromatin condenses and becomes tightly coiled to form visible chromosomes
    • Nuclear envelope disassembles into vesicles
    • Centrosomes move to opposite poles of the cell and spindle fibers begin to form
  • Metaphase
    • Chromosomes align at the equatorial plane of the cell
    • Spindle fibers attach to the kinetochores of each sister chromatid
  • Anaphase
    • Sister chromatids separate and are pulled towards opposite poles of the cell by the shortening of the spindle fibers
    • Each pole receives a complete set of chromosomes
  • Telophase
    • Nuclear envelope re-forms around each set of chromosomes
    • Chromosomes decondense back into chromatin
    • Cytokinesis begins to divide the cytoplasm and organelles into two daughter cells (cleavage furrow in animal cells, cell plate in plant cells)

Cyclins and CDKs in regulation

• Cyclins
  • Regulatory proteins that control the progression of the cell cycle
  • Concentrations fluctuate throughout the cell cycle with specific cyclins peaking at different phases
  • Bind to and activate cyclin-dependent kinases (CDKs)
• Cyclin-dependent kinases (CDKs)
  • Serine/threonine kinases that phosphorylate target proteins involved in cell cycle progression
  • Require binding to cyclins for activation and substrate specificity
• Cyclin-CDK complexes
  • Specific cyclin-CDK complexes form at different stages of the cell cycle to regulate key events
  • Phosphorylate substrates that promote cell cycle progression (transcription factors, replication proteins)
  • Examples:
    • Cyclin D-CDK4/6 complex promotes entry into G1 by phosphorylating the retinoblastoma protein (Rb)
    • Cyclin E-CDK2 complex promotes the G1/S transition by phosphorylating proteins involved in DNA replication initiation
    • Cyclin A-CDK2 complex promotes S phase progression by phosphorylating proteins involved in DNA replication and repair
    • Cyclin B-CDK1 complex promotes the G2/M transition by phosphorylating proteins involved in nuclear envelope breakdown and chromosome condensation

Cell cycle checkpoints

• G1 checkpoint
  • Ensures the cell has reached a sufficient size and has adequate nutrients and growth factors to proceed with cell division
  • Checks for DNA damage and arrests the cell cycle if damage is detected to allow for repair
  • The p53 tumor suppressor protein plays a key role in triggering cell cycle arrest in response to DNA damage
• G2 checkpoint
  • Ensures DNA replication is complete and no errors or damage have occurred
  • Checks for DNA damage and prevents entry into mitosis if damage is present to allow for repair
  • The checkpoint kinase Chk1 is activated in response to DNA damage and phosphorylates the phosphatase Cdc25, preventing activation of the cyclin B-CDK1 complex
• Spindle assembly checkpoint (SAC)
  • Occurs during metaphase of mitosis
  • Ensures proper attachment of spindle fibers to the kinetochores of each sister chromatid
  • Prevents the onset of anaphase until all chromosomes are properly aligned at the equatorial plane
  • The SAC proteins Mad2 and BubR1 inhibit the anaphase-promoting complex/cyclosome (APC/C) until proper spindle attachment is achieved
• Checkpoints are crucial for maintaining genomic stability
  • Prevent the propagation of mutations and chromosomal abnormalities to daughter cells
  • Allow time for DNA repair mechanisms to fix damage before cell cycle progression
  • Ensure equal distribution of genetic material to daughter cells during mitosis

Dysregulation and cancer development

• Cell cycle dysregulation can lead to uncontrolled cell division and proliferation
  • Mutations in genes that regulate the cell cycle can disrupt normal control mechanisms
    • Oncogenes: Genes that promote cell cycle progression when overactivated (cyclins, CDKs, growth factor receptors)
    • Tumor suppressor genes: Genes that inhibit cell cycle progression when inactivated (p53, Rb, p16)
  • Overexpression of growth factors or growth factor receptors can stimulate excessive cell division (epidermal growth factor receptor/EGFR in lung cancer)
• Consequences of cell cycle dysregulation
  • Accumulation of mutations and genomic instability due to unchecked cell division
  • Evasion of apoptosis (programmed cell death) leading to survival of abnormal cells
  • Sustained proliferative signaling resulting in continuous cell division
  • Enabling of replicative immortality by overcoming normal cellular senescence
• Relationship to cancer development
  • The hallmarks of cancer are acquired through various cell cycle dysregulation events
  • Uncontrolled cell division leads to the formation of tumors and cancer progression
  • Mutations in cell cycle regulators are common drivers in many types of cancer (p53 mutations in over 50% of cancers)
  • Targeting cell cycle regulators is a promising strategy for cancer therapy (CDK4/6 inhibitors in breast cancer treatment)