The cell cycle is a precisely programmed series of events that enables a cell to duplicate its contents and divide into two daughter cells. It consists of interphase (G1, S, G2 phases) and mitosis (M phase). Progression through the cell cycle is regulated by cyclins and cyclin-dependent kinases (CDKs). CDK activity is controlled by association with cyclins, CDK inhibitors, and phosphorylation. Checkpoint pathways like the G1/S, G2, and spindle assembly checkpoints ensure replication and division errors are corrected before progression. Deregulation of these checkpoint pathways can lead to genomic instability and carcinogenesis.

3.  CELL CYCLE
 A precisely programmed series of events that enables a cell to
duplicate its contents and to divide into two daughter cells
 The phases of cell cycle
 G1, S , G2, and M.
 A fifth stage - G0 - the resting, non proliferating state of cells
that have withdrawn from the active cell cycle.

4. • There are three stages of interphase: G1 , S and G2
• Cells spend most of their lives in interphase
• G1 phase - cell growth , protein synthesis
• S phase - DNA and centrosomes are replicated
• G2 phase - energy replenishment , mitotic specific proteins
synthesis, cytoskeleton dismantling and additional growth

5. Image Source - le.ac.uk/vgec/topics/cell-cycle/the-cell-cycle-schools-and-colleges

7. • During the PROPHASE of mitosis,
the chromosomes , which were
invisible microscopically during
interphase , begin to condense
and become visible, while the
centrosomes at the poles of the
cell begin to assemble .
• During METAPHASE , the
chromosomes align along a plane
that bisects the cell and become
attached to the microtubule
fibers of the mitotic spindle . At
the same time, the nuclear
membrane has disappeared.
Image source - cellular division- Jayant , Meyers, Geddis,and Priano (2014)

8. • During ANAPHASE , the
chromatids are pulled apart by
the mitotic spindle to the
opposite poles of the cell
• During TELOPHASE, shortly after
the chromatids cluster into the
two sets , they de-condense and
a new nuclear membrane forms
around each set of chromatids .
At the same time, during the
process of cytokinesis, the
cytoplasm of the mother cell
divides, yielding two daughter
cells.
Image source - cellular division- Jayant , Meyers, Geddis,and Priano (2014)

10. CELL CYCLE CLOCK
• A network of interacting proteins—a signal-processing circuit—that decides
the cell’s fate.
Image source - The biology of cancer Robert A. Weinberg

11. • Cyclins and cyclin-dependent kinases constitute the core components of the
cell cycle clock
• Cyclins undergo cyclical changes in their concentration which depends on the
transcription of its gene and by the degradation of subsequent regulated
proteins
• The concentration of CDKs doesn’t fluctuate
• Cyclin & CDK exert their effect by phosphorylating the target proteins
• Dephosphorylation is an important mechanism for resetting the cell for another
round of the cell cycle.

13. Image source - The biology of cancer Robert A. Weinberg

14. source - The biology of cancer Robert A. Weinberg

15. • Signaling pathways that sense and induce a cellular response to DNA
damage.
• The components are DNA damage sensors, signal transducers, or
effectors.
• A decatenation checkpoint in late G2 prevents entrance into M until the
pair of DNA helices replicated in the previous S phase have been
untangled from one another.
• Disruption of checkpoint function leads to genomic and chromosomal
instability leading to mutations that can induce carcinogenesis

17. • CDKs are serine/ threonine kinases - sequentially regulate progression of
cell through the cell cycle via phosphorylation.
• 4 mechanisms of CDK regulation :-
- Association with cyclins
- Association with CDK inhibitors
- Addition of phosphate groups that activate CDK activity
- Addition of phosphate groups that inhibit CDK activity
• Regulators of the cell cycle are required because of the precise window of
time and hence ‘disappearance’ of a factor is as important as its
‘appearance’.

18. Lauren Pecornio- Molecular biology of cancer -mechanisms, targets , and therapeutics 3rd edition (2012)

19. ASSOCIATION WITH CYCLINS
• The binding of cyclins to their partner cdk causes a conformational
change in the cdk and this allows binding of a protein substrate and
correct positioning of ATP.
• Some cyclins increases the affirnity of cdks to specific substrates.
• The amounts of cyclin protein vary through the cell cycle that are
modified by transcriptional regulation of the cyclin genes and by protein
degradation
• The ubiquitinization of cyclins induces its degradation by the proteasome
which prevents further activity of cdks.

20. ASSOCIATION WITH INHIBITORS
• 2 Families of inhibitors are involved in regulating cyclin–cdk activity:
- p16 INK 4a family
- p21 Cip/Kip family
• INK Protein binds to cdk 4/6 and interferes with its binding to cyclin D
• Cip/Kip family of inhibitors interact with both cyclins and their associated
cdks (mainly with cdk2 and cyclin E) and disable kinase activity.
• Mitogenic stimulation followed by cyclin D synthesis , corresponding cdk
sequester inhibitors of the cip /kip family facilitates the cyclin E –cdk 2
activation
• ubiquitin-mediated degradation of inhibitors ensures that the inhibitors
are present during a specific period of time during the cell cycle.

21. REGULATION BY PHOSPHORYLATION
• This involves both activation and inhibition.
• Two phosphorylation sites on the amino-terminal end are inhibitory when
phosphorylated
• tyrosine kinase, wee1- phosphorylates Thr14 and Tyr1 which are located
deep within the ATP-binding site of the cdk and phosphorylation of these
sites physically interferes with ATP binding.
• Two steps are required for cdks to become active:
Dephosphorylation of the inhibitory phosphate groups by cdc25
phosphatases
Phosphorylation of a central threonine residue- Thr161 by cdk-activating
kinase (CAK).

22. source - The biology of cancer Robert A. Weinberg

23. Lauren Pecornio- Molecular biology of cancer -mechanisms, targets , and therapeutics 3rd edition (2012)

24. • Blocks entry to M phase of those cells with DNA damage or those not
completing S phase
Lauren Pecornio- Molecular biology of cancer -mechanisms, targets , and therapeutics 3rd edition (2012)

25. • Activation of the G2 checkpoint results in the inhibition of Cdc25s by
Chk1/2.
• Specific Cdc25s (type B and C) are important in the G2–M phase
transition.
• DECATENATION G2 CHECKPOINT
- detangles intertwined daughter chromatids after DNA synthesis
- enables chromatid separation during anaphase of mitosis
- Topoisomerase II – releases tortional stress by breaking ds -DNA
to allow unwinding (key enzyme in decatenation check point)

26. • Also known as spindle assembly check point
• It is a signaling cascade that ensures correct chromosomal segregation
during mitosis and the production of two genetically identical nuclei.
• Unattached chromatid pairs attract inhibitors of Anaphase promoting
complexes
• Targets degradation proteins (securin)  separase sister chromatids
separation during anaphase
• APC inhibition stops after all chromatid pairs are attached to spindle fibres

27. Lauren Pecornio- Molecular biology of cancer -mechanisms, targets , and therapeutics 3rd edition (2012)

28. Sorce - Angius, G.; Tomao, S.; Stati, V.; Vici, P.; Bianco, V.; Tomao, F. Prexasertib, a checkpoint kinase inhibitor: From preclinical data to clinical development. Cancer Chemother. Pharmacol. 2020, 85, 9–20. [Google Scholar]
[CrossRef

29. source - The biology of cancer Robert A. Weinberg

30. source - The biology of cancer Robert A. Weinberg

31. Table - Basic and Clinical Pharmacology, 13th Ed. Cancer Chemotherapy Edward Chu, MD, & Alan C. Sartorelli, PhD
Image-www.amboss.com/us/knowledge/Chemotherapeutic_agents#anker=Zaf1779dab451b9a98d11834d04e33388