AP Biology 4.6-4.7: Cell Cycle and Regulation

Cell cycle

The ordered sequence in which a cell grows, duplicates its DNA and other components, and divides into two daughter cells.

What are the two major stages of the eukaryotic cell cycle?

Interphase, consisting of $G_1$, S, and $G_2$, and the M phase, consisting of mitosis and cytokinesis.

Interphase

The portion of the cell cycle in which the cell grows, performs normal functions, replicates DNA, and prepares for division. It includes $G_1$, S, and $G_2$.

What occurs during the $G_1$ phase?

The cell grows, resumes biosynthetic activity, produces proteins and organelles, and evaluates whether conditions are suitable for DNA replication.

What is the relationship between chromosome number and DNA content during S phase?

DNA content doubles because each chromosome is replicated into two sister chromatids, but chromosome number does not double because the sister chromatids remain joined as one chromosome until anaphase.

What occurs during the $G_2$ phase?

The cell grows and synthesizes proteins needed for mitosis, including components involved in spindle formation. DNA is checked for completion and damage before mitosis begins.

What is the $G_0$ phase?

$G_0$ is a quiescent state in which a cell has exited the active cell cycle and stopped dividing. Some specialized cells remain there for very long periods or permanently, whereas other cells can reenter the cycle in response to signals.

How can cell-cycle timing vary among cells?

Cell-cycle duration differs greatly among cell types and organisms. Rapidly dividing mammalian cells may complete a cycle in about 24 hours, whereas early fruit-fly embryos can complete nuclear divisions in about 8 minutes because cytokinesis is delayed.

In a rapidly dividing human cell with a 24-hour cycle, approximately how long do $G_1$, S, $G_2$, and M last?

Approximately $9$ hours in $G_1$, $10$ hours in S, $4.5$ hours in $G_2$, and $0.5$ hours in M.

Mitosis

Nuclear division in which replicated chromosomes are separated into two genetically equivalent nuclei. Its stages are prophase, prometaphase, metaphase, anaphase, and telophase.

What are the major events of the stages of mitosis?

During prophase, chromosomes condense and the spindle begins forming. During prometaphase, the nuclear envelope breaks down and spindle microtubules attach to kinetochores. During metaphase, chromosomes align at the cell's equator. During anaphase, sister chromatids separate toward opposite poles. During telophase, nuclear envelopes reform around the two chromosome sets.

Cytokinesis

Division of the cytoplasm and other cellular components into two daughter cells. Animal cells form a cleavage furrow, whereas plant cells form a cell plate.

How do cytokinesis mechanisms differ between animal and plant cells?

In animal cells, the plasma membrane constricts inward to form a cleavage furrow. In plant cells, vesicles form a cell plate that develops into a separating structure between the daughter cells.

Why can increasing cell size stimulate cell division?

As a cell grows, its surface-area-to-volume ratio decreases, reducing the efficiency of exchanging materials with the environment. Division produces smaller cells with a more favorable surface-area-to-volume ratio.

How do external signals regulate cell division?

Growth factors and hormones can stimulate division, while cell crowding, loss of nearby cells, or insufficient growth-promoting signals can alter division. The cell integrates these external signals before entering or continuing the cycle.

What is a cell-cycle checkpoint?

A checkpoint is a regulatory point at which progression to the next stage can be halted until required conditions are satisfied, such as adequate cell resources, intact DNA, or correct chromosome attachment.

Where are the three major eukaryotic cell-cycle checkpoints located?

They occur near the end of $G_1$, at the $G_2$/M transition, and during metaphase near the metaphase-to-anaphase transition.

$G_1$ checkpoint (restriction point)

The checkpoint near the end of $G_1$ that evaluates cell size, nutrient and protein reserves, external growth signals, and DNA integrity. Passing it generally commits the cell to completing the division cycle.

What happens if a cell fails the $G_1$ checkpoint?

The cell may pause to correct the problem, remain arrested in $G_1$, or enter $G_0$ until conditions improve. It does not proceed into S phase while essential requirements are unmet.

$G_2$ checkpoint

The checkpoint before mitosis that verifies adequate cell resources, complete chromosome replication, and the absence of significant DNA damage.

What happens if DNA replication is incomplete or damaged at the $G_2$ checkpoint?

The cell cycle is halted while the cell attempts to finish replication or repair the DNA. If the damage cannot be resolved, cell death may be triggered.

M checkpoint (spindle checkpoint)

The metaphase checkpoint that verifies correct attachment of sister-chromatid kinetochores to spindle microtubules before anaphase begins.

What attachment condition is required at the M checkpoint?

Each sister-chromatid pair must be firmly connected through its kinetochores to spindle fibers associated with opposite poles, allowing the sisters to be pulled apart accurately.

Why must the M checkpoint prevent anaphase until spindle attachments are correct?

Sister-chromatid separation during anaphase is effectively irreversible. Incorrect attachment could distribute chromosomes unevenly and produce genetically abnormal daughter cells.

What is the role of APC activation at the metaphase-to-anaphase transition?

Activation of the anaphase-promoting complex (APC) helps trigger sister-chromatid separation after the spindle checkpoint is satisfied, allowing the cell to proceed from metaphase to anaphase.

Positive regulation of the cell cycle

Regulation that promotes progression through checkpoints. The principal positive regulators are cyclins and cyclin-dependent kinases (Cdks).

Cyclins

Regulatory proteins whose concentrations rise and fall during the cell cycle. Their changing abundance controls when active cyclin–Cdk complexes form.

Cyclin-dependent kinases (Cdks)

Protein kinases whose levels are relatively stable but whose activity depends on binding a cyclin and receiving activating phosphorylation. Active Cdks phosphorylate target proteins that promote cell-cycle progression.

How does a cyclin–Cdk complex become fully active?

A Cdk binds its appropriate cyclin and is then phosphorylated at specific sites by another kinase. The active complex phosphorylates proteins needed to pass a checkpoint.

Why do cyclin concentrations, rather than Cdk concentrations, largely control cyclin–Cdk activity?

Cdk levels remain relatively constant, while cyclin levels fluctuate. Therefore, cyclin accumulation and degradation determine when sufficient active cyclin–Cdk complexes are present.

How are the G1/S–Cdk, S–Cdk, and M–Cdk activities coordinated?

G1/S–Cdk activity commits the cell to a new cycle, S–Cdk activity initiates DNA replication, and M–Cdk activity promotes entry into mitosis and spindle assembly. Their sequential activation helps ensure that major events occur in the correct order.

Why are cyclins degraded after a cell passes a checkpoint?

Degradation removes the cyclin needed for the previous transition, lowering the corresponding cyclin–Cdk activity and helping establish directionality between cell-cycle phases.

Negative regulation of the cell cycle

Regulation that stops or delays cell-cycle progression when conditions are unfavorable or cellular damage is detected. Important negative regulators include Rb, p53, and p21.

Cdk inhibitors

Negative regulatory molecules that prevent full Cdk or cyclin–Cdk activity. They maintain a cell-cycle arrest until the specific problem or incomplete event they monitor has been resolved.

Tumor-suppressor protein

A protein that restrains cell proliferation, promotes repair or arrest after damage, or triggers apoptosis when necessary. Loss-of-function mutations in such proteins can permit uncontrolled cell division.

Retinoblastoma protein (Rb)

A tumor-suppressor protein that helps regulate the $G_1$/S transition by controlling transcription factors such as E2F. Its active form prevents expression of genes required for DNA synthesis.

How does active Rb prevent the $G_1$-to-S transition?

Dephosphorylated Rb binds E2F and prevents E2F from activating genes needed for DNA replication and S-phase entry.

How does cell growth release Rb's inhibition of E2F?

As the cell grows and receives appropriate signals, Rb becomes progressively phosphorylated and inactivated. It releases E2F, allowing transcription of genes that promote the $G_1$/S transition.

p21

A Cdk inhibitor induced by p53 in response to cellular stress or DNA damage. By inhibiting cyclin–Cdk complexes, p21 reduces the likelihood that the cell will enter S phase.

What is the role of p53 at the $G_1$ checkpoint?

When DNA damage is detected, p53 can halt the cell cycle and activate DNA-repair pathways. If repair fails, p53 can initiate apoptosis, preventing replication of severely damaged DNA.

How does p53 indirectly inhibit cyclin–Cdk complexes?

Increased p53 stimulates production of p21. p21 binds to and inhibits cyclin–Cdk complexes, enforcing a cell-cycle arrest before S phase.

What is the consequence of a nonfunctional p53 protein?

Cells with damaged DNA may fail to arrest, repair the damage, or undergo apoptosis and can continue dividing. This increases the likelihood of mutation accumulation and cancer development.

Compare the effects of p53/p21 and Rb on cell-cycle progression.

p53 and p21 respond primarily to stress or DNA damage and inhibit progression toward S phase. Rb mainly links cell-growth conditions to the $G_1$/S transition by restraining E2F until sufficient growth-related phosphorylation occurs.

What is the molecular significance of phosphorylation in cell-cycle regulation?

Phosphorylation can change a protein's conformation and activity. Cdks use phosphorylation to activate target proteins that advance the cell cycle, while phosphorylation of Rb inactivates its inhibition of E2F.

Apoptosis

Programmed cell death that eliminates cells with irreparable damage or other serious problems, helping prevent damaged cells from continuing to divide.

How does apoptosis protect an organism from cell-cycle errors?

Apoptosis eliminates cells whose DNA damage cannot be repaired, preventing those cells from replicating damaged chromosomes and passing mutations to their descendants.

What is cellular senescence?

Cellular senescence is a generally permanent cell-cycle arrest, often caused by DNA damage or external stress. It can serve as an alternative to apoptosis for preventing a damaged cell from dividing.

Why do checkpoint failures promote cancer?

A failed checkpoint can allow cells with damaged DNA, incomplete replication, or misattached chromosomes to divide. Mutations can then accumulate in descendant cells, potentially producing uncontrolled proliferation.

Why can failure of a single cell-cycle regulator have either limited or severe effects?

Multiple regulatory mechanisms may control the same event, allowing one defective regulator to be partly compensated for. However, if the regulator affects several processes or combines with other defects, uncontrolled proliferation or cell death can result.

A cell has adequate nutrients and is large enough, but its DNA is damaged during $G_1$. What is the expected response?

The $G_1$ checkpoint should halt progression, with p53 promoting repair and p21 inhibiting cyclin–Cdk complexes. If repair is unsuccessful, p53 may induce apoptosis rather than allow S-phase entry.

A cell completes DNA replication but one sister-chromatid pair is not attached correctly to spindle microtubules. Which checkpoint is affected, and what happens?

The M, or spindle, checkpoint is not satisfied. The cell should delay anaphase until the kinetochore attachments are corrected.

A mutation causes Rb to remain permanently active. How would this affect the cell cycle?

Rb would continue binding E2F, preventing transcription of genes required for the $G_1$/S transition. The cell would tend to remain arrested before DNA replication.

A mutation causes Rb to be unable to bind E2F. What is the likely consequence?

E2F could remain active even when cell-growth conditions are inadequate, causing inappropriate expression of S-phase genes and increasing the risk of uncontrolled proliferation.