9.1 Cell cycle phases and checkpoints

Cell cycle phases and checkpoints are crucial for understanding how cells grow and divide. These processes control when and how cells replicate their DNA and split into two daughter cells. Knowing these steps helps us grasp why some cells are more sensitive to radiation than others.

Checkpoints act like quality control, making sure everything's ready before moving to the next phase. When these checkpoints fail, it can lead to cancer. This topic connects to radiosensitivity by showing how cells in different cycle phases respond differently to radiation damage.

Phases of the Cell Cycle

Interphase and Mitosis

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• Cell cycle consists of interphase (G1, S, G2 phases) and mitosis (M phase), followed by cytokinesis
• G1 phase involves cell growth, protein synthesis, and preparation for DNA replication
  • Cells increase in size and produce necessary proteins for DNA replication
  • Duration varies depending on cell type (hours to days)
• S phase encompasses DNA replication, duplicating the cell's genetic material
  • DNA synthesis occurs, resulting in two identical sets of chromosomes
  • Takes approximately 8-10 hours in a typical mammalian cell
• G2 phase continues cell growth and protein synthesis, preparing for mitosis
  • Cells synthesize proteins needed for chromosome condensation and spindle formation
  • Typically lasts 3-4 hours in mammalian cells

Mitotic Phase and Cytokinesis

• Mitosis (M phase) divided into prophase, metaphase, anaphase, and telophase
  • Prophase: Chromatin condenses into visible chromosomes
  • Metaphase: Chromosomes align along the cell's equator
  • Anaphase: Sister chromatids separate and move to opposite poles
  • Telophase: Nuclear envelopes reform around daughter chromosomes
• Cytokinesis physically divides the cytoplasm, typically occurring at the end of telophase
  • In animal cells, a contractile ring of actin and myosin pinches the cell in two
  • Plant cells form a cell plate that grows outward to separate daughter cells
• Some cells enter quiescent state called G0, temporarily or permanently exiting cell cycle
  • Examples include neurons and skeletal muscle cells (permanent G0)
  • Liver cells can re-enter the cycle from G0 when stimulated (temporary G0)

Checkpoints in Cell Cycle Regulation

Major Cell Cycle Checkpoints

• G1/S checkpoint (restriction point) controls entry into S phase
  • Influenced by growth factors (platelet-derived growth factor) and cell size
  • Ensures sufficient resources for DNA replication and cell division
• Intra-S checkpoint monitors DNA replication and responds to replication stress
  • Activated by stalled replication forks or DNA damage during S phase
  • Slows DNA synthesis and prevents late origin firing
• G2/M checkpoint ensures complete DNA replication and repair before mitosis
  • Prevents cells with unreplicated or damaged DNA from entering mitosis
  • Activated by incomplete replication or DNA damage (double-strand breaks)
• Spindle assembly checkpoint (SAC) operates during mitosis
  • Ensures proper chromosome attachment to mitotic spindle before anaphase
  • Prevents chromosome missegregation and aneuploidy

Checkpoint Functions and Consequences

• Checkpoints trigger cell cycle arrest, allowing time for repair mechanisms
  • Arrest can be temporary (allowing repair) or permanent (senescence or apoptosis)
  • Example: DNA damage activates p53, leading to p21 expression and cell cycle arrest
• Failure of checkpoint mechanisms leads to genomic instability and cancer development
  • Mutations in checkpoint proteins (p53, ATM) found in many cancers
  • Chromosomal aberrations and aneuploidy result from defective checkpoints

Cell Cycle Control Mechanisms

Cyclin-CDK Complexes and Inhibitors

• Cyclin-dependent kinases (CDKs) and cyclins central to cell cycle control
  • CDKs are serine/threonine kinases activated by binding to cyclins
  • Cyclin levels fluctuate throughout the cell cycle, regulating CDK activity
• Different cyclin-CDK complexes active during specific cell cycle phases
  • Cyclin D-CDK4/6 in G1 phase promotes G1/S transition
  • Cyclin E-CDK2 initiates S phase and DNA replication
  • Cyclin A-CDK2 regulates S phase progression
  • Cyclin B-CDK1 drives mitotic entry and progression
• CDK inhibitors (CKIs) regulate cyclin-CDK activity and induce cell cycle arrest
  • p21 and p27 (CIP/KIP family) inhibit a broad range of cyclin-CDK complexes
  • INK4 family (p16, p15, p18, p19) specifically inhibit CDK4/6

Key Regulatory Proteins and Pathways

• Retinoblastoma protein (pRb) and E2F transcription factors control G1/S transition
  • pRb binds and inhibits E2F in G1
  • Cyclin D-CDK4/6 phosphorylates pRb, releasing E2F to activate S phase genes
• Tumor suppressor p53 crucial for cell cycle arrest and apoptosis
  • Activated by DNA damage, oncogene activation, or cellular stress
  • Induces p21 expression, leading to CDK inhibition and cell cycle arrest
• Anaphase-promoting complex/cyclosome (APC/C) regulates mitotic progression
  • E3 ubiquitin ligase that targets cyclin B and securin for degradation
  • Cdc20 and Cdh1 co-activators determine APC/C substrate specificity
• Protein kinases ATM and ATR key sensors of DNA damage
  • ATM responds primarily to double-strand breaks
  • ATR activated by single-stranded DNA at stalled replication forks
  • Both activate checkpoint signaling cascades (CHK1, CHK2) to arrest cell cycle

Cell Cycle Dysregulation in Cancer

Genetic Alterations and Proliferation

• Mutations in proto-oncogenes and tumor suppressors lead to uncontrolled proliferation
  • Oncogene activation (RAS, MYC) promotes continuous cell division
  • Tumor suppressor inactivation (p53, pRb) removes growth restraints
• Overexpression of cyclins or CDKs results in aberrant cell cycle progression
  • Cyclin D1 amplification common in breast and esophageal cancers
  • CDK4 amplification found in melanoma and sarcomas
• Inactivation of CKIs allows unchecked cell division
  • p16 deletion frequent in pancreatic cancer and melanoma
  • p27 downregulation associated with poor prognosis in various cancers

Genomic Instability and Cancer Progression

• Loss of function in checkpoint proteins allows division of damaged cells
  • p53 mutations found in over 50% of human cancers
  • ATM mutations cause ataxia-telangiectasia and increased cancer risk
• Chromosomal instability arises from defects in mitotic checkpoint proteins
  • Mutations in SAC components (MAD2, BUB1) lead to aneuploidy
  • Cohesion defects cause premature sister chromatid separation
• Dysregulation of apoptotic pathways prevents elimination of abnormal cells
  • Overexpression of anti-apoptotic proteins (BCL-2) in follicular lymphoma
  • Inactivation of pro-apoptotic proteins (BAX) in colon cancer
• Increased replicative potential through telomere maintenance mechanisms
  • Telomerase activation in ~85% of human cancers
  • Alternative lengthening of telomeres (ALT) in some sarcomas and gliomas
• Cell cycle dysregulation understanding led to targeted cancer therapies
  • CDK4/6 inhibitors (palbociclib) for breast cancer treatment
  • Mitotic spindle poisons (paclitaxel) disrupt cell division in various cancers