Recording-2025-02-22T16_48_45.263Z

Overview of the Cell Cycle

The focus of this series of lectures will be on the cell cycle, a complex yet fundamental process in all cells, which involves a series of well-coordinated events leading to cell division and replication. While students may already have some understanding of the basic stages of the cell cycle from previous classes, this course will delve deeper into how cells orchestrate the timing and coordination of various processes, emphasizing the molecular and environmental mechanisms that ensure correct execution. Understanding the cell cycle is crucial for comprehending cellular growth and proliferation in multicellular organisms, as well as the implications for cancer biology when regulation fails.

Cell Division Requirements

The primary purpose of cell division is to duplicate and accurately segregate genetic material. In addition to DNA replication, cells must grow and appropriately distribute membrane-bound organelles such as mitochondria, lysosomes, and the endoplasmic reticulum to daughter cells. During cell division, significant changes are necessary within various cellular compartments, including the nucleus and cytoplasm, which must occur in a tightly regulated manner to ensure the success of division and the viability of daughter cells.

Key Changes During Cell Division

• DNA Replication: This occurs during the S phase, where each strand of DNA is copied to ensure that each daughter cell receives a complete set of genetic information. Accurate DNA replication is essential to prevent mutations that can lead to cancer.

• Mitotic Spindle Assembly: Necessary for proper chromosome alignment and segregation during mitosis. The mitotic spindle is formed from microtubules and is vital for pulling apart sister chromatids to opposite poles of the cell.

• Cytoskeleton Reorganization: Changes in microtubule and actin structures are essential for maintaining cell shape during division and facilitating processes such as chromosomal movement and cytokinesis.

Regulation of the Cell Cycle

The cell cycle is divided into distinct phases: G1 (Gap 1), S (Synthesis), G2 (Gap 2), and M (Mitotic) phases. G1, S, and G2 represent the interphase, while M phase encompasses both mitosis and cytokinesis. Understanding cell cycle progression involves recognizing two major components:

• Molecular Triggers: These function as engines driving the cell cycle forward, including various cyclin-dependent kinases (CDKs) that are activated at specific points during the cycle to ensure events occur in an orderly sequence.

• Checkpoint Components: These act as brakes to halt progression under unfavorable conditions, allowing cells to repair damage or correct errors before proceeding.

Molecular Triggers vs. Checkpoints

• Molecular Triggers: Specific types of cyclins bind to and activate CDKs at various points during the cell cycle, ensuring that the cell only moves on to the next stage when it is ready. For example, cyclin D activates CDK4 and CDK6 to allow progression through the G1 phase.

• Checkpoints: Critical evaluation points in the cycle where cells assess their internal and external conditions, such as detecting DNA damage or incomplete replication. Major checkpoints include G1/S (during G1 to assess DNA integrity), G2/M (ensuring DNA is replicated and undamaged before mitosis), and the metaphase/anaphase transition (verifying all chromosomes are correctly attached to the spindle apparatus before separation).

External Regulation and Mitogenic Signals

In many organisms, the cell cycle is tightly regulated by external factors known as mitogens, which are nutrients or signals that promote cell division by triggering receptor activation on the cell surface. One key regulator is the RB Protein: In the absence of mitogens, the RB protein is active and inhibits transcription factors necessary for cell cycle entry. Upon mitogen binding to surface receptors, signaling pathways lead to the inactivation of RB, allowing the cell cycle to progress through the G1 phase into S phase.

Cyclin-Dependent Kinases (CDKs)

• G1/S CDK Complexes: These complexes drive the cell into the S phase, promoting DNA replication once conditions are favorable.

• Sequential Activation: The activation of early-CDK complexes is necessary for the activation of subsequent complexes; for example, G1/S CDK activates S CDK, which is crucial for initiating DNA synthesis and preparing for mitosis.

CDK Activity Regulation

The activity of CDKs is precisely regulated by the availability of their associated cyclins. Each type of cyclin is produced and degraded at specific phases of the cycle to control CDK activity systematically.

• Periodic Degradation of Cyclins: Mechanisms such as the ubiquitin-proteasome pathway ensure cyclins are periodically degraded, thus influencing the activation of CDKs. For instance, the S cyclin activates the S CDK for DNA replication, followed by its degradation to allow M cyclin activation for progression into mitosis.

• Negative Feedback Loop: The activation of CDKs can lead to the degradation of their associated cyclins, mediated by the anaphase-promoting complex (APC), which marks cyclins for destruction to ensure proper timing in the cell cycle.

Importance of Checkpoints

Checkpoints in the cell cycle are vital for identifying and correcting mistakes, especially regarding DNA damage or chromosomal abnormalities. Major checkpoints include:

• G1/S Checkpoint: Assesses DNA integrity prior to replication and determines if conditions are favorable for DNA synthesis.

• G2/M Checkpoint: Ensures that all DNA is fully replicated and undamaged before the cell enters mitosis, preventing propagation of damage.

• Metaphase/Anaphase Transition: Checks that all chromosomes are correctly attached to the spindle apparatus before separation during anaphase, thereby ensuring that each daughter cell receives the correct chromosome number.

Role of p53 in DNA Damage Response

The p53 Protein serves a critical function as a tumor suppressor by mediating the cellular response to DNA damage. It activates the production of CDK inhibitors, such as p21, to halt cell cycle progression and allow for DNA repair.

• Consequences of p53 Inactivation: Loss of p53 function can lead to unchecked cell proliferation and increased risk of cancer due to the accumulation of DNA mutations and genomic instability.

Mechanisms of Chromosome Segregation

During anaphase, various processes must accurately separate sister chromatids to ensure that each daughter cell inherits the correct genetic information. The coordinated actions of M CDK and the APC are essential:

• Sister Chromatid Separation: Mediated by the enzyme separase, which is activated following the degradation of its inhibitory protein, securin, allowing sister chromatids to be pulled apart.

Cytokinesis

Following mitosis, cytokinesis must occur to physically separate the two daughter cells. This process involves:

• Formation of the Contractile Ring: Composed of actin and myosin filaments, the contractile ring constricts the cell membrane, facilitating separation of the cells.

• Regulation by RhoA: This GTPase directs the assembly of the contractile ring and influences the placement of the cleavage furrow during cytokinesis.

Organelle Distribution

During cell division, membrane-bound organelles, such as the Golgi apparatus and endoplasmic reticulum, undergo significant changes to ensure equitable distribution between daughter cells. This involves fragmentation of the Golgi apparatus and bisecting the ER, allowing each daughter cell to receive the necessary organelles for functionality.

In conclusion, a detailed understanding of the regulation of the cell cycle, including checkpoints, molecular triggers, and the coordination of multiple cellular structures, is essential for the proper division and functioning of eukaryotic cells. This knowledge is fundamental not only for understanding normal cell proliferation but also for recognizing the deviations that can lead to diseases such as cancer.