Untitled Quiz

Cell Cycle Overview

• The cell cycle is a series of events leading to cell duplication and division.
• In bacteria, cell growth and DNA replication occur throughout most of the cell cycle. Duplicated chromosomes are distributed to daughter cells along the plasma membrane.
• Eukaryotic cell cycles are more complex. DNA replication happens in only one phase of the cycle. Replicated chromosomes are distributed to new nuclei by a series of events before cell division.

Eukaryotic Cell Cycle

• Consists of four coordinated processes: cell growth, DNA replication, distribution of duplicated chromosomes to daughter cells, and cell division.
• Eukaryotic cell cycles are divided into four discrete phases: M, G1, S, and G2.
• M phase includes mitosis, usually followed by cytokinesis.
• The cell grows throughout interphase (G1, S, and G2). A typical human cell in culture divides approximately every 24 hours.
• Mitosis and cytokinesis last about an hour, representing 5% of the cell cycle.

Cell Cycle Phases in Cultured Cells

• G1: About 10-11 hours
• S: About 7.5 hours
• G2: About 3.5- 4 hours
• M: About 1 hour
• Total time: Around 22 hours for cultured human cells.

Cell Cycle Variations

• Duration of phases varies considerably between different cell types.
• Budding yeasts, for example, complete the full cycle in about 90 minutes.
• Early embryonic cell cycles are extremely short (30 minutes or less) shortly after fertilization. Growth doesn't occur, instead focusing on rapid division and cytoplasm division
• In adult animals, some cells (e.g., nerve cells) don't divide at all after a certain period.
• Other cells divide occasionally, as needed to replace lost cells (e.g., skin fibroblasts, liver cells). These cells enter a quiescent stage (G0) where they remain metabolically active, but not proliferating unless stimulated by extracellular signals.

Regulation of the Cell Cycle

• The progression through the division cycle depends on external cues from the environment and internal signals.
• These internal signals monitor and coordinate events during different cell cycle phases.
• Availability of growth factors controls the animal cell cycle. If growth factors are unavailable, the cell enters a resting phase (G0).

Cell Cycle Checkpoints

• Control mechanisms ensuring proper progression of the eukaryotic cell cycle.
• Checkpoints detect damage to DNA from external factors or DNA replication problems, triggering a DNA damage response.
• Checkpoints also monitor chromosome attachment to spindle fibers.
• Several checkpoints throughout the cell cycle guarantee complete genomes are passed to daughter cells.
• Coordination between different phases of the cell cycle depends on cell cycle checkpoints that prevent the cell from entering the next phase until the prior phase's events are complete.

Types of Cell Cycle Checkpoints

• G1/S checkpoint
• Intra S checkpoint
• G2/M checkpoint
• Spindle assembly checkpoint

Regulating DNA Replication

• MCM proteins enable DNA replication only once per cycle by binding to origins of replication; after the replication initiates in the S phase these proteins are displaced.
• The association of MCM proteins with DNA is blocked by protein kinases in later phases of the cell cycle.

Regulators of Cell Cycle Progression

• Protein Kinases and Cell Cycle Regulation
• Families of Cyclins and Cyclin-Dependent Kinases
• Growth Factors and the Regulation of G1 Cdks
• DNA Damage Checkpoints

Cyclins

• A family of proteins controlling the progression of the cell cycle by activating cyclin-dependent kinase enzymes (Cdk's).
• Each cell cycle stage has its own cyclin types.

Cyclin-Dependent Kinases (CDKs)

• Protein kinases associated with regulatory subunits (cyclins).
• Humans have more than 10 distinct Cdk types, a few involved in cell cycle control.
• Cdk1, Cdk2, Cdk4, and Cdk6 are important for cell cycle progression. Cdk activity depends on the regulatory subunit (called cyclin).
• Cdk7 activates other Cdks.
• Cdk2/cyclin E and entry into S phase is inhibited by Cdk inhibitor p27.

G1/S Checkpoint and G1/S Regulation

• pRb/ E2F
• Rb is masked by inactive E2F (in default settings).
• CDK4 and CDK6 (with Cyclin D) phosphorylate Rb, inactivating and degrading it.
• E2F is now free, promoting the production of proteins necessary for DNA replication to proceed from G1 to S phase.

Growth Factors and G1 CDKs

• In its hypo-phosphorylated form, Rb binds to the E2F family, repressing their target genes.
• Phosphorylation of Rb releases E2F which allows it to activate genes necessary for cell cycle progression.
• Growth factor signaling reduces p27 levels, contributing to Cdk2/cyclinE activation and subsequently initiating DNA replication

DNA Damage Checkpoints

• ATM and ATR protein kinases are activated by damaged or unreplicated DNA.
• Phosphorylation and activation of CHK1 and CHK2
• Cdc25A and Cdc25C are inhibited preventing Cdk1 and Cdk2 activation consequently blocking progression through the cell cycle stages.
• p53 plays a major role in cell cycle arrest. Increased p53 levels trigger p21 production inhibiting Cdk2, stopping cell cycle, and allowing repair of DNA damage.

The Events of M Phase

• Stages of Mitosis
• Cdk1/Cyclin B and Progression to Metaphase
• The Spindle Assembly Checkpoint and Progression to Anaphase
• Cytokinesis

Stages of Mitosis (in animal cells)

• Prophase- chromosome condensation; centrosomes move to opposite sides initiating spindle formation
• Prometaphase- nuclear envelope breakdown; spindle microtubules attach to kinetochores
• Metaphase- chromosomes (with their sister chromatids ) are aligned in the center of the cell
• Anaphase- sister chromatids separate and move to opposite poles
• Telophase- nuclear envelope re-forms; chromosomes decondense.
• Cytokinesis - division of the cytoplasm, creating two new interphase daughter cells.

Spindle Assembly Checkpoint

• Monitors chromosome alignment on the metaphase spindle.
• Mad/Bub proteins bind Cdc20(required for APC complex activation).
• Unaligned chromosomes prevent the APC from activating and initiates delay in anaphase progression.
• APC ubiquitinates Cyclin B and is essential for the cell to move ahead into and finish mitosis.