AP Syllabus focus:
‘Some disruptions activate pathways that trigger apoptosis, allowing damaged or dangerous cells to undergo programmed cell death.’
Cells constantly monitor division. When disruptions create unrepairable damage or dangerous behavior, checkpoint signaling can switch from “pause and repair” to apoptosis, eliminating the cell to protect the organism.
When cell-cycle disruption leads to apoptosis
Cell-cycle progression depends on accurate DNA replication, chromosome attachment to the spindle, and intact checkpoint control. If disruption is severe, the cell can activate programmed cell death rather than risk propagating mutations or abnormal chromosome numbers.
Common disruption signals that push cells toward apoptosis include:
Extensive DNA damage (e.g., double-strand breaks) that cannot be repaired before division
Replication stress (stalled replication forks, depleted nucleotides) leading to persistent checkpoint activation
Mitotic/spindle errors (improper kinetochore attachment, prolonged metaphase arrest)
Oncogenic hyperproliferation signals that drive inappropriate entry into the cycle, triggering protective death pathways
Apoptosis (what it is and why it matters)
Apoptosis: A genetically controlled, energy-requiring form of cell death that dismantles a cell in an orderly way, packaging contents into membrane-bound fragments that are removed with minimal inflammation.
By removing a compromised cell, apoptosis helps maintain tissue function and prevents damaged genomes from being passed to daughter cells.
Key molecular control: deciding between arrest and death
Checkpoint pathways can produce two broad outcomes:
Cell-cycle arrest long enough for repair (temporary survival)
Apoptosis when damage is irreparable or the cell is unsafe (permanent removal)
A central integration point is p53, a transcription factor activated by cellular stress.
p53: A tumour-suppressor transcription factor that responds to cellular damage by inducing genes for cell-cycle arrest, DNA repair, or apoptosis.
When activated strongly or persistently, p53 shifts gene expression toward apoptosis, including production of pro-apoptotic proteins that act on mitochondria.
Cells also balance opposing regulators:
Pro-apoptotic factors (promote death) vs anti-apoptotic factors (promote survival)
The balance often converges on the mitochondrial outer membrane, a key “commitment step” for many apoptotic responses to cell-cycle disruption.
Core apoptosis pathways connected to cell-cycle disruption
Two major signaling routes can execute apoptosis; disruptions in the cell cycle most commonly activate the intrinsic (mitochondrial) pathway.
Diagram comparing the extrinsic (death-receptor) and intrinsic (mitochondrial) apoptosis pathways, emphasizing the key complexes (DISC and apoptosome) and their convergence on caspase-3 activation. It highlights how cytochrome c release and apoptosome assembly activate initiator caspases that then trigger executioner caspases, producing irreversible cellular dismantling. Source
Intrinsic (mitochondrial) pathway: typical for internal damage
Internal stress signals (especially DNA damage) promote mitochondrial membrane permeabilization, releasing factors that activate proteases called caspases.
Caspase: A protease (cysteine-aspartate protease) that cleaves specific proteins to initiate and execute apoptosis in a controlled cascade.
A simplified sequence:
Disruption detected (e.g., severe DNA damage, prolonged checkpoint activation)
p53 (and related stress pathways) increases pro-apoptotic signals
Mitochondrial outer membrane becomes permeable
Cytochrome c is released into the cytosol
Cytochrome c helps assemble an activation complex (often termed the apoptosome)
Initiator caspases activate executioner caspases
Executioner caspases dismantle the cell by targeted protein cleavage
Cell-cycle relevance: the longer a cell remains stuck at a checkpoint with unresolved problems, the more likely it is to accumulate pro-death signals and commit to this pathway.
Extrinsic (death receptor) pathway: external “remove this cell” signals
Some cells undergoing abnormal cycling can also be eliminated when neighboring cells or immune cells provide external death signals via membrane receptors. This route:
Begins at cell-surface death receptors
Activates initiator caspases directly
Converges on executioner caspases and the same dismantling steps
What apoptosis looks like (cellular outcomes)
Apoptosis produces distinct, orderly changes that limit damage to surrounding tissue:
Histology image showing apoptotic bodies (indicated by arrows) in tissue, illustrating the fragmented, membrane-bound remnants produced during apoptosis. This reinforces that apoptosis packages cellular contents into discrete bodies that can be rapidly cleared by neighboring cells or phagocytes, limiting inflammation. Source
Cell shrinkage and chromatin condensation
Membrane blebbing while the plasma membrane remains largely intact
Fragmentation into apoptotic bodies (membrane-bound pieces)
Rapid engulfment by neighboring cells or phagocytes, typically avoiding inflammation
In the context of cell-cycle disruption, these outcomes ensure that cells with dangerous genetic or division defects are removed before they can form abnormal clones or interfere with tissue architecture.
FAQ
Apoptotic cells expose “eat-me” signals (notably phosphatidylserine) on the outer membrane.
Phagocytes bind these signals directly or via bridging proteins, then engulf apoptotic bodies and digest them in lysosomes.
Many viruses produce proteins that block apoptosis by:
Inhibiting p53 activity
Mimicking anti-apoptotic Bcl-2-like proteins
Directly inhibiting caspases
This prolongs host-cell survival to increase viral replication.
Some therapies intentionally create DNA damage or replication stress to push tumour cells past a threshold where checkpoint signalling favours apoptosis.
Sensitivity depends on whether p53 and downstream apoptotic machinery remain functional.
If apoptosis is impaired, cells with serious division errors may survive despite disruption.
This increases the chance of accumulating additional mutations and persisting as abnormal clones rather than being eliminated.
Common assays include:
Annexin V staining (detects phosphatidylserine exposure)
TUNEL assay (detects fragmented DNA ends)
Measuring activated caspases (e.g., cleaved caspase-3) using antibodies
Practice Questions
Explain how apoptosis helps protect an organism when a cell has severe DNA damage during the cell cycle. (2 marks)
Removes the damaged cell to prevent passing mutations to daughter cells (1)
Controlled dismantling/packaging prevents harm to neighbouring cells and limits inflammation (1)
Describe how severe DNA damage can lead to apoptosis, including the roles of p53, mitochondria, and caspases. (6 marks)
DNA damage activates a stress/checkpoint response that stabilises/activates p53 (1)
p53 promotes expression of pro-apoptotic factors and/or reduces survival signalling (1)
Mitochondrial outer membrane becomes permeable and releases cytochrome c (1)
Cytochrome c promotes formation of an activation complex (e.g., apoptosome) that activates initiator caspases (1)
Initiator caspases activate executioner caspases in a cascade (1)
Executioner caspases cleave key proteins causing orderly cell dismantling into apoptotic bodies for clearance (1)
