The document summarizes key aspects of the cell cycle: 1) The cell cycle is the series of events by which a cell duplicates its genome and divides into two identical daughter cells, and consists of interphase (G1, S, G2 phases) and mitosis. 2) Progression through the cell cycle is regulated by checkpoints at G1, G2 and metaphase to ensure accurate DNA replication and chromosome segregation. 3) The activity of cyclins, cyclin-dependent kinases and their inhibitors control progression through the different cell cycle phases. 4) Cancer results from defects in cell cycle regulation and checkpoint genes that lead to uncontrolled cell proliferation.

1. Cell Cycle and its implications
Dr. Lokendra Kunwar
MD Resident
Department of Clinical Oncology

2. Cell Cycle
• Sequence of events by which cell duplicates its genome and divides
into two identical daughter cells.
• Length of the Cell Cycle- depends on the type of cell that is dividing;
most of the cells in human body complete cell cycle in 24hrs.

3. Phases of Cell Cycle
• Interphase: Gap 1 (G1) phase – Gap 0 (G0)
Synthesis (S) phase
Gap 2 (G2) phase
• Mitosis phase:
Karyokinesis - Prophase, Metaphase, Anaphase, Telophase
Cytokinesis

5. Interphase
• Longest phase of the cell cycle.
• Preparation phase for redivison of a newly divided cell
• Series of changes take place in newly formed cell and its nucleus,
before it becomes capable of division again.
• 3 distinct phases
G1 phase
S phase
G2 phase.

6. Gap 1 (G1) phase
• First phase within the interphase
• Period of rapid growth
• Cell grows in preparation for DNA replication by synthesizing mRNA
and proteins, and certain intracellular components, such as
centrosomes undergo replication.
• Takes up about 1/3rd of the time of cell cycle.
• Determines whether a cell commits to divide or leaves the cell cycle.
• Ends after the cell move on to the S phase.

7. Synthesis (S) phase
• Follows G1 phase
• DNA replication occurs
• Strands of chromatin are copied, so that 2 new identical strands of
DNA are made; each chromosome now has 2 sister chromatids.
• Tightly regulated and widely conserved

8. Gap 2 (G2) phase
• Gap between DNA synthesis and mitosis.
• Period of rapid growth and cell prepares itself for mitosis.
• Proteins and enzymes related to cell division are synthesized.
• Stores energy which would be used during the division phase.
• G2 phase ends with the start of M phase.

10. G0 phase
• Resting phase where the cell has left the cell cycle and has stopped
dividing.
• Quiescent / Senescent state.
• Non proliferative cells generally enter this phase.
• Some cells remain quiescent for long periods of time like neurons.
• Some cells enter G0 phase semi permanently like hepatic and renal
cells.

11. Mitosis (M) phase
• Mitosis is the division of nucleus and cytoplasm of a parent cell into
two genetically identical daughter cells.
• Consists of Karyokinesis and Cytokinesis

12. Cell cycle phases

13. Cell Cycle Checkpoints
• Progression of cell cycle is highly regulated in certain points.
• These critical regulatory points of cell cycle are called Cell cycle
checkpoints.
• It ensures that:
- Genome is intact
- Conditions are appropriate for a cell to divide
- Genetic material is replicated completely in a cell cycle
- Chromosomes are correctly oriented in the metaphase plate
- All chromosomes are correctly attached to the spindle fibres.

14. 3 checkpoints;
• G1 checkpoint (restriction checkpoint)
• G2 checkpoint (G2-M DNA damage checkpoint)
• Metaphase M checkpoint (Spindle assembly checkpoint)

15. G1 checkpoint
• Also called restriction point
• Operates at the end of G1 phase
• Checks whether:
- conditions are favorable for cell to undergo replication
• Checks DNA damage and directs the DNA repair mechanism to rectify
any DNA damage
• Mediated by cyclin E/CDK2 complex and Rb-E2F protein.

16. G2 checkpoint
• Operates at the end of G2 phase
• Checks for:
- Any damage to the DNA that might have occurred during DNA
replication
- Whether DNA is replicated completely
• Monitors the level of proteins and growth factors
• If any of the above factors are not satisfactory, G2 checkpoint holds
the cell at G2 phase and initate machineries to rectify the problems.

17. M checkpoint
• Operates at the end of metaphase.
• Checks for:
- Integrity of the spindle apparatus
- Correct orientation of chromosomes in metaphase plate
- Whether all chromosome are properly attached to the spindle fibres
• If chromosomes are not correctly attached to the spindle apparatus,
this checkpoint will stop the cell cycle.

19. Regulation of Cell Cycle
• Cyclins
• Cyclin Dependent Kinases (CDK)
• Cyclin Dependent Kinase Inhibitors (CDKI)
• Rb protein and E2F

20. Cyclins
• They are the family of proteins which regulates the cell cycle.
• Their concentration and expression cycles/varies during the cell cycle.
• Several types of cyclins are active during different phases of cell cycle
which bind to different types of CDKs and causes phosphorylation of
CDKs.
• Cyclins are synthesized and then actively degraded using ATP at
specific points in the cell cycle.

22. Cyclin Dependent Kinase
• CDKs are enzymes which activate the proteins required for
progression through the cell cycle and its checkpoints
• Inactive on their own but becomes active when attached to cyclin by
forming cyclin-CDK complex.
• Cyclin-CDK complexes then phosphorylates or attaches phosphate
group to certain domain on target proteins.
• The regulated activity of CDKs is essential for the transitions from G1
to S and from G2 to M.

24. Cyclin Dependent Kinase Inhibitors
• Inhibits CDKs
• Cell cycle is negatively controlled by CDKI
• Involved in cell cycle arrest at different phases of cell cycle.

25. Rb protein
• Initially identified as the product of the prototype tumor suppressor
gene, Rb.
• Prevents excessive cell division by regulating G1 checkpoint and
inhibiting cell cycle progression.
• Rb protein is normally bound to a transcription factor called E2F.
• Phosphorylation of Rb protein prevents its association with E2F,
thereby permitting E2F activation which causes transcription of genes
required for entry into S phase.

27. Cancer and cell cycle
• Cancer is a disease of abnormal proliferation and uncontrolled cell
division.
• Cell cycle misregulation and checkpoint genes mutation cause defect
in DNA synthesis and eventually cause cancer.
• Genes in which mutation gives rise to gain of function, leading to
malignancy are proto-oncogenes.
• Genes that give rise to loss of function mutations, leads to malignancy
are tumor suppressor genes.

28. • Proto-oncogenes- N ras, K ras, Her 2 neu, EGFR, ALK, N-myc, c-myc,
bcl2
• Tumor suppressor genes- Rb, p53, APC, BRCA, NF1, NF2, VHL
- Rb gene – Retinoblastoma, Osteosarcoma, Small cell lung cancer,
Breast cancer.
- p53 gene (Li Fraumeni Syndrome) - Sarcomas, Breast Ca, Leukemia,
Adrenal Ca.

29. Chemotherapy and cell cycle
• Rapidly growing neoplasia with a short cell cycle and larger
proportion of cells in S phase are highly responsive to chemotherapy.
• Many chemotherapeutic agents are cell cycle specific and produce
cytotoxic effect to tumor cells.
• Various drugs used in combination chemotherapy act at different
phases of cell cycle to produce maximum cell kill.

31. Radiotherapy and cell cycle
• G0, G1, S phase- Radioresistant.
• G2 and M phase- Radiosensitive.

32. THANK YOU