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

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

 

🧬 Cell Cycle & Regulation – MCQs (CSIR-NET Level)

1. Which cyclin–Cdk complex is required for the G2 → M transition? Cyclin D–Cdk4/6 Cyclin E–Cdk2 Cyclin A–Cdk2 Cyclin B–Cdk1

2. The restriction point (R-point) in mammalian cells is mainly regulated by: Cyclin A–Cdk2 Cyclin D–Cdk4/6 and Rb–E2F pathway Cyclin B–Cdk1 p53 and p21

3. Which checkpoint ensures proper spindle attachment before anaphase? G1/S checkpoint G2/M checkpoint Spindle Assembly Checkpoint DNA replication checkpoint

4. INK4 family of Cdk inhibitors specifically inhibits: Cdk1 Cdk2 Cdk4 and Cdk6 Cdk5

5. The “Guardian of the Genome” is: Rb E2F p53 APC/C

6. Anaphase-Promoting Complex (APC/C) functions as: Protein kinase Ubiquitin ligase DNA helicase Transcription factor

7. Which process occurs only during S phase? Chromosome condensation DNA replication and histone synthesis Spindle assembly Cytokinesis

8. Loss of Rb protein leads to: G0 arrest Uncontrolled E2F activity Inhibition of Cyclin D Activation of apoptosis only

9. Which drug is a Cdk4/6 inhibitor used in cancer therapy? Taxol Cisplatin Palbociclib Colchicine

10. Which kinase activates Chk1/Chk2 during DNA damage response? ATM / ATR APC/C Cdk5 Wee1