Cell Cycle and Its Regulation

Introduction

The cell cycle is a fundamental process through which cells grow, duplicate their genetic material, and divide into two daughter cells. It ensures genetic stability and proper cell proliferation, which is critical for development, tissue repair, and reproduction. Dysregulation of the cell cycle is closely associated with diseases such as cancer.

Phases of the Cell Cycle

The cell cycle is broadly divided into two main stages: Interphase and M phase (Mitosis + Cytokinesis).

1.     Interphase (90% of cycle duration)

o    G1 phase (Gap 1): Cell grows, accumulates nutrients, synthesizes RNA and proteins.

o    S phase (Synthesis): DNA replication occurs; histone proteins are synthesized.

o    G2 phase (Gap 2): Preparation for mitosis; cell checks for DNA damage and ensures all DNA is replicated.

2.     M phase (Mitosis + Cytokinesis)

o    Prophase → Prometaphase → Metaphase → Anaphase → Telophase.

o    Followed by Cytokinesis: division of cytoplasm into two daughter cells.

3.     G0 Phase (Quiescent state)

o    Non-dividing, resting phase. Cells like neurons remain in G0 permanently.

Checkpoints in Cell Cycle Regulation

Checkpoints are surveillance mechanisms that ensure fidelity of cell division:

Checkpoint	Controlled By	Function
G1/S Checkpoint (Restriction Point)	Cyclin D–Cdk4/6, Rb–E2F pathway	Ensures DNA integrity before replication begins
S-phase Checkpoint	ATR/Chk1 pathway	Monitors ongoing DNA replication and repair
G2/M Checkpoint	Cyclin B–Cdk1 (MPF), p53, Wee1/Myt1	Ensures DNA is fully replicated and undamaged before mitosis
Spindle Assembly Checkpoint (SAC)	APC/C, Mad2, Bub proteins	Ensures proper attachment of chromosomes to spindle before anaphase

 

Key Regulators of Cell Cycle

1.     Cyclins and Cyclin-Dependent Kinases (Cdks):

o    Cdks are serine/threonine kinases activated by binding to cyclins.

o    Different cyclin–Cdk complexes drive progression through each phase.

Phase	Cyclin–Cdk Complex
G1 → S	Cyclin D–Cdk4/6, Cyclin E–Cdk2
S → G2	Cyclin A–Cdk2
G2 → M	Cyclin B–Cdk1 (Maturation Promoting Factor, MPF)

2.     Cdk Inhibitors (CKIs):

o    Two families:

§  INK4 family (p15, p16, p18, p19) → specifically inhibit Cdk4/6.

§  Cip/Kip family (p21, p27, p57) → broadly inhibit cyclin–Cdk complexes.

3.     Retinoblastoma Protein (Rb):

o    Acts as a brake in G1 phase by binding E2F transcription factors.

o    Cyclin Cdk phosphorylation of Rb releases E2F, allowing S-phase entry.

4.     p53 (Guardian of Genome):

o    Responds to DNA damage by activating p21 (a CKI), which halts the cell cycle.

o    If damage is irreparable, p53 triggers apoptosis.

5.     Anaphase-Promoting Complex (APC/C):

o    A ubiquitin ligase that degrades securin and cyclins.

o    Ensures progression from metaphase to anaphase and mitotic exit.

Cell Cycle Regulation and Cancer

• In cancer, cell cycle checkpoints are often defective.
• Overactive cyclins (e.g., Cyclin D1 amplification) or loss of CKIs (like p16 deletion) drive uncontrolled proliferation.
• Mutations in p53 or Rb are common hallmarks in many cancers.
• Thus, targeting cell cycle regulators is an important therapeutic strategy (e.g., Cdk4/6 inhibitors like Palbociclib).

Conclusion

The cell cycle is a highly ordered and tightly regulated process involving cyclins, Cdks, CKIs, and checkpoint proteins. Its regulation maintains genomic stability, while its dysregulation leads to uncontrolled cell growth and cancer. Understanding these mechanisms is not only central to developmental biology but also provides a foundation for targeted cancer therapies, making it a vital area for CSIR-NET preparation.

📖 Reference Books for CSIR-NET:

• Alberts et al., Molecular Biology of the Cell
• Lodish et al., Molecular Cell Biology
• Bruce Alberts’ figures for visual understanding

MCQs on Cell Cycle and Regulation

1.Which of the following cyclin–Cdk complexes is required for the G2 → M transition?

a) Cyclin D–Cdk4/6
b) Cyclin E–Cdk2
c) Cyclin A–Cdk2
d) Cyclin B–Cdk1

Answer: d) Cyclin B–Cdk1
Explanation: The Cyclin B–Cdk1 complex, also called Maturation Promoting Factor (MPF), is essential for entry into mitosis.

2.The restriction point (R-point) in mammalian cells is regulated mainly by:

a) Cyclin A–Cdk2
b) Cyclin D–Cdk4/6 and Rb–E2F pathway
c) Cyclin B–Cdk1
d) p53 and p21

Answer: b) Cyclin D–Cdk4/6 and Rb–E2F pathway
Explanation: In G1, phosphorylation of Rb by Cyclin D–Cdk4/6 releases E2F transcription factor, allowing the cell to pass the restriction point and enter S-phase.

3.Which checkpoint ensures that all chromosomes are properly attached to the spindle before separation?

a) G1/S checkpoint
b) G2/M checkpoint
c) Spindle Assembly Checkpoint (SAC)
d) DNA replication checkpoint

Answer: c) Spindle Assembly Checkpoint (SAC)
Explanation: SAC monitors kinetochore–microtubule attachment and delays anaphase onset until proper alignment is achieved.

4.The INK4 family of Cdk inhibitors (CKIs) specifically inhibits:

a) Cdk1
b) Cdk2
c) Cdk4 and Cdk6
d) Cdk5

Answer: c) Cdk4 and Cdk6
Explanation: INK4 proteins (p15, p16, p18, p19) prevent Cyclin D from activating Cdk4/6, blocking progression through G1.

5.Which protein is known as the “Guardian of the Genome”?

a) Rb
b) E2F
c) p53
d) APC/C

Answer: c) p53
Explanation: p53 prevents the propagation of damaged DNA by halting the cell cycle (via p21) or inducing apoptosis.

6.The Anaphase-Promoting Complex (APC/C) primarily functions as:

a) A serine/threonine kinase
b) A ubiquitin ligase complex
c) A DNA helicase
d) A transcription factor

Answer: b) A ubiquitin ligase complex
Explanation: APC/C marks securin and cyclins for degradation, allowing sister chromatid separation and mitotic exit.

7.Which of the following occurs only during S phase?

a) Chromosome condensation
b) DNA replication and histone synthesis
c) Centrosome duplication and spindle assembly
d) Cytokinesis

Answer: b) DNA replication and histone synthesis
Explanation: DNA duplication along with synthesis of histones occurs in S phase to package the replicated DNA.

8.Loss-of-function mutation in Rb protein leads to:

a) Arrest at G0 phase
b) Continuous release of E2F and uncontrolled cell cycle entry
c) Inhibition of Cyclin D–Cdk4 activity
d) Activation of p53 pathway

Answer: b) Continuous release of E2F and uncontrolled cell cycle entry
Explanation: Rb normally restrains E2F. Without functional Rb, cells bypass G1 checkpoint and proliferate uncontrollably.

9.Which of the following drugs is a Cdk4/6 inhibitor used in cancer therapy?

a) Taxol
b) Cisplatin
c) Palbociclib
d) Colchicine

Answer: c) Palbociclib
Explanation: Palbociclib inhibits Cyclin D–Cdk4/6, preventing Rb phosphorylation and blocking cell cycle progression in cancers.

10.Which kinase is involved in DNA damage response by activating Chk1/Chk2 pathway?

a) ATM/ATR
b) APC/C
c) Cdk5
d) Wee1

Answer: a) ATM/ATR
Explanation: ATM responds to double-strand breaks, ATR to replication stress, both activating Chk1/Chk2 to halt the cycle.

Cell Cycle Checkpoints – Quick Revision

Checkpoint	Phase	Key Regulators	Main Function
G1/S (Restriction Point)	End of G1	Cyclin D–Cdk4/6, Rb–E2F, p53–p21	Ensures cell has sufficient nutrients, growth factors, and no DNA damage before DNA replication.
S-phase checkpoint	During S	ATR, Chk1, Cdc25	Monitors DNA replication stress, prevents collapsed replication forks.
G2/M checkpoint	End of G2	Cyclin B–Cdk1 (MPF), Wee1 kinase, Cdc25 phosphatase, p53	Ensures DNA replication is complete and DNA damage is repaired before mitosis.
Spindle Assembly Checkpoint (SAC)	Metaphase–Anaphase	APC/C, Mad2, Bub proteins, securin–separase	Ensures all chromosomes are properly attached to spindle microtubules before chromatid separation.
DNA Damage checkpoint	Throughout	ATM, ATR, Chk1/Chk2, p53	Detects DNA breaks and halts cycle for repair or induces apoptosis if damage is severe.

Key Mnemonic:

• G1/S → Growth & nutrients check
• S → DNA replication fidelity
• G2/M → DNA repair before mitosis
• SAC → Chromosome alignment check