Cell cycle.

1. By
Dr.N.Sreekanth
DNB-RT

2. • The cell cycle or cell-division cycle is the series of
events that take place in a cell leading to its
division and duplication of its DNA to produce
daughter cells.
• There are two types of cell division.
– Mitosis
• Growth and repair
• Produces diploid cells identical to each other and the parent
cell
– Meiosis
• Sexual reproduction
• Produces haploid cells different to each other and the parent
cell.
Somatic cells
Germ cells

3. Eukaryotic Cell Populations
Germ cells -Unlimited proliferation by meiotic division.
(Unlike cancer cells, these cells form immortal cell lines through
meiotic division)
Stem cells -These cells have two functions.
Proliferation & Differentiation
(Unlike cancer cells, these cells can only pass through a limited
number of cell cycles)
Partially differentiated cells - These have a limited capacity for
proliferation, and their daughter cells are fully differentiated with
no proliferative ability.
Fully differentiated cells -These cells never proliferate.

5. MITOSIS

6. Prophase
• The nuclear membrane
and endoplasmic
reticulum disappear.
• The chromosomes
shorten and thicken.
• Centrosomes move
towards opposite poles.
• The nucleolus disappears.
• Spindle cells form from
the poles to the center.

7. Metaphase
• The chromosomes
shorten and thicken
further.
• Sister chromatids are
kept together using
centromeres.
• The chromosomes are
arranged side-by-side in
a row in the equatorial
plane.
• The chromosomes hold
on to spindle cells with
their centromeres.

8. Anaphase
• The contraction and
relaxation movements
of spindle cells break
the centromeres that
lock the chromatids
together.
• The sister chromatids
are separated from
each other and are
moved to opposite
poles.

9. Telophase
• The chromosomes stop moving.
• The chromosomes unwind their
helices and become chromatins.
• The nucleolus reappears.
• RNA and protein syntheses
start.
• Spindle cells disappear.
• The nuclear membrane forms,
and the endoplasmic reticulum
takes on a shape again.
• Vital events restart in the cell.
• Cytogenesis occurs, and division
finishes.

10. Interphase
• The interphase is the preparation phase for
the redivision of a cell.
• It is the longest phase of the eukaryotic cell
cycle.
• The interphase is divided into THREE stages.
(G0/G1, S, G2)

12. G0 phase
• Most cells in an adult are not in the process of
cell division.
• They enter an inactive period called G0, a
phase outside of the cell cycle.
• Mitogens or growth factors can, however,
induce cells in G0 to re-enter the cell cycle.

13. G1 Phase (Gap1)
• This occurs just after cytogenesis.
• This is the stage where matter transportation,
synthesis, lysis reactions, organelle
production, RNA synthesis and tissue
functions continue at their highest levels.
• It is the longest stage.

14. S Phase (Synthesis)
• DNA is duplicated and the number of
chromatins doubles (Replication).
• The most intense protein synthesis is
performed at this stage.
• The order of centromere duplication is
observed.

15. G2 Phase (Gap2)
• Enzymes related to division are synthesized.
• The number of organelles increases.
• DNA synthesis finishes, but RNA synthesis
continues.
• Centrosome synthesis finishes, and these
centrosomes start moving towards opposite
poles.

16. • The most radiosensitive stages during the cell
cycle are the early G2 and M stages
– The radiosensitivity of a cell is four-fold greater
during the mitotic phase than during the
interphase.
• Radioresistance is high in the S, late G1 and
G0 phases.
– The resistance of the S phase is due to the large
amounts of synthesis enzymes present, which
have the ability to rapidly repair DNA.

17. CHECK POINTS
• Cell cycle checkpoints, a series of biochemical
signaling pathways that sense and induce a
cellular response to DNA damage, are
important for maintaining the integrity of the
genome.
• There are 3 important check points
– G1 check point
– G2 check point
– M check point

18. • The G1 checkpoint leads to the arrest of the
cell cycle in response to DNA damage,
ensuring that DNA damage is not replicated
during S phase.
• The G2 checkpoint leads to the arrest of the
cell cycle in response to damaged and/or
unreplicated DNA to ensure proper
completion of S phase.
• The M checkpoint leads to the arrest of
chromosomal segregation in response to
misalignment on the mitotic spindle.

20. Tim Hunt Paul Nurse Lee Hartwell
Nobel Prize in Physiology or Medicine in 2001
The prize was received for studies on the regulation of the cell cycle during which
the cyclins were discovered.

21. • The components of the checkpoints are
proteins that act as DNA damage
sensors, signal transducers, or effectors.
• Disruption of checkpoint function leads
to genomic and chromosomal instability
leading to mutations that can induce
carcinogenesis.

22. • The passage of the cell through the different
phases of the cell cycle is coordinated and
regulated by a set of proteins called cyclins
and their associated cyclin- dependent
kinases (cdks).
• Cyclins are regulatory subunits of their cdks.

23. • Cyclins were so named because of the cyclical
changes in their concentrations that occur
over a series of cell divisions.
• The concentration of cyclin protein is
dependent on the transcription of its gene
and by subsequent regulated protein
degradation.

25. • The cyclin–cdk complexes exert their
effect by phosphorylating target proteins
• Binding of a cyclin to its cdk partner,
cyclin induces a conformational change
in the catalytic subunit of the cdk
revealing its active site.
• The concentration of cdks does not
fluctuate during the cell cycle.

26. • The pairing of cyclins to the cdks is highly
specific.
–Cyclin D - cdks 4/6
–Cyclin E - cdk2
–Cyclin A - cdk2
–Cyclins A,B - cdk1

28. Cyclin D is the first cyclin to be synthesized.
• Cyclin D - cdks 4/6  drives through G1.
• Cyclin E - cdk2  G1 to S phase transition.
• Cyclin A–cdk2  S phase progression.
• Cyclins A,B–cdk1  G2 & G2 to M phase
transition.

29. G1 Check point
• The retinoblastoma (RB) protein is an important
target of cyclin D–cdks 4/6 and a key regulator of
the G1 to S phase transition.
• RB exerts its effects by protein–protein
interactions with the E2F transcription factor and
HDACs.
Hypophosphorylated RB
inactivates E2F and
recruits HDACs.

30. • The activity of RB is regulated by phosphorylation via different
cyclins–cdks.
• Signaling pathway for the growth factor EGF results in the
transcriptional activation of the cyclin D gene and allows
progression through the restriction point.
Repression is relieved for some genes such as cyclin E

31. Phosphorylated RB releases E2F leading to Expression of its
target genes, such as cyclin A, thymidylate synthase, and
dihydrofolate reductase, that are important for S phase

33. G2 Check point
• The G2 checkpoint blocks entry into M phase
in cells that have incurred DNA damage in
previous phases or have not correctly
completed S phase.
• The G2 checkpoint is induced by DNA damage
and aberrant DNA synthesis and blocks entry
into M phase.
• Specific Cdc25s (type B and C) are important
in the G2–M phase transition.

36. • There is also a decatenation G2 checkpoint
that is involved chromatid separation during
anaphase of mitosis.
• Topoisomerase II, an enzyme that can release
torsional stress by making double-strand DNA
breaks to allow unwinding, is key in the
decatenation G2 checkpoint.

38. Mitotic Check point
• The mitotic checkpoint (also known as the spindle assembly
checkpoint) is a signaling cascade that ensures correct
chromosomal segregation during mitosis and the production of
two genetically identical nuclei.
(Prevents mis-segregation of chromosomes during anaphase)
• The Aurora kinases (A, B, and C) regulate important aspects of
mitosis, including chromosome segregation and the spindle
checkpoint.
• They are serine/threonine kinases that phosphorylate target
proteins, which play a role in chromosome structure and
spindle assembly.

40. Mechanisms of cdk regulation
• Cdks are regulated by association with cyclins,
inhibitors, and by activating and inhibitory
phosphorylation.

41. Association with cyclins

42. Association with inhibitors

44. Regulation by phosphorylation
The tyrosine kinase, wee1, phosphorylates Thr14 and Tyr15.

45. Regulation by phosphorylation

47. • Four stages: G1, S phase, G2, and M phase.
• G1, S, and G2 make up the part of the cycle called
interphase.
• The genetic material of a cell is replicated in S
phase (DNA synthesis).
• M phase involves the partitioning of the cell to
produce two daughter cells and includes mitosis
and cytokinesis.
• G1 and G2 are ‘gaps’ preceding the S and M
phases during which time the cell prepares for
the next phase.

48. • Aurora kinase A
– Localizes to centrosomes during interphase
– Upregulated at the beginning of mitosis and relocates to the
spindle poles and spindle microtubules
– Role in centrosome maturation and assembly of the spindle
apparatus
• Aurora kinase B activity is highest later in mitosis.
• Role in bipolar spindle attachment to chromosomal
centromeres, and the spindle checkpoint and monitoring of
chromosomal segregation and cytokinesis.
• Aurora kinase C is active during late mitosis and localizes to
spindle poles.