The cell cycle is the ordered series of events that leads to cell division into two daughter cells. It consists of four main phases: G1, S, G2, and M. Checkpoints ensure each step is completed before progression. Cyclins activate CDKs at specific phases - G1 cyclins activate G1 CDKs which promote DNA replication by phosphorylating Rb and activating E2Fs. S-phase CDKs activate DNA replication origins. Mitotic CDKs promote mitotic events like spindle formation and chromosome condensation. Completion of mitosis involves chromosome segregation and cyclin degradation to inactivate CDKs and allow cell division.

1. CELL CYCLE :- AN
OVERVIEW

2. What is cell cycle?
The ordered series of events that lead to the division of cell into two daughter cells each
containing chromosomes identical to the parent cell.
PHASES IN CELL CYCLE
G1-S-G2-M-CYTOKINESIS

3. CELL DIVISION CONTROL
High fidelity and accuracy are required to ensure that DNA replication is carried out
correctly and each daughter cell inherits correct no. of chromosomes.
WHAT GOVERNS THE EVENTS IN CELL CYCLE?
Checkpoints!!!
The surveillance mechanisms that prevent the initiation of each step in cell division
until the previous has been completed.

4. CYCLINS
• Cyclins are so named because their concentrations change during the cell cycle.
• They bind to and activate CDK
• They are present only during the cell cycle stage they trigger and are absent in others.
• They are different from each other in protein sequence, but all of them contain a conserved
100-amino-acid region known as the cyclin box.

5. CDKs
CDKs are regulated by :-
1.cyclin binding
2.activating and inhibitory phosphorylation.
Together, these regulatory events ensure that CDKs are active only at the appropriate cell cycle stage.

6. G1 CDKs
• G1 CDKs activate members of E2F transcription factors.
• During G1 E2Fs are held inactive through their association with retinoblastoma protein (Rb) until G1 CDKs
activate E2Fs by phosphorylating and inactivating Rb.
• E2Fs than activates genes encoding many proteins involved in DNA synthesis.
• Also stimulate the translation of genes encoding G1/S and S phase cyclins.
• This is one of the events responsible for passage through RESTRICTION POINT.
• S phase CDKs and M-CDKs maintain Rb protein in the phosphorylated state throughout the S, G2 and
early M phase.
• After ANAPHASE (late M phase) a fall in cyclin-CDK activities leads to dephosphorylation of Rb.
• Thus, hypo-phosphorylated Rb is available to inhibit E2F during early G1 of the next cycle.
• Henceforth, G1/S CDKs activity remains low until cell decides to enter a new cell- cycle.

7. S-Phase
• G1/S CDKs turn off the machinery that degrades S phase cyclins during exit from mitosis
and G1 and induce the degradation of a CDK Inhibitor that inhibits S-Phase CDKs.

8. S Phase Regulation
• When G1/S CDKs levels are high and CKIs of S-CDKs are destroyed it is then S-phase CDKs and
a second protein kinase DDK activates MCM HELICASE and recruits DNA polymerases to the
sites of ORI (origin of replication).
• A protein complex known as ORC (origin replication complex) is associated with DNA
replication.
• ORC and two initiation factors cdc6 and cdt1 associate , to load replicative Helicases.
• MCM helicases can be loaded at low CDK activity during exit from mitosis and early G1.
• Thus, their activation/phosphorylation is triggered by S-Phase CDKs.

10. COHESINS ESTABLISH LINKAGES BETWEEN REPLICATED DNA MOLECULES
• The protein complexes that establish linkages between sister chromatids are called cohesins.
They are composed of four subunits: Smc1, Smc3, Scc1 (sometimes called Rad21), and Scc3.
• Smc1 and Smc3 are members of the SMC protein family, which is characterized by long
coiled-coil domains that are flanked by a globular domain containing ATPase activity.
• The ATPase domains interact with Scc1 and Scc3 and, together, form a ring structure.
• These rings of cohesin embrace one or both copies of the replicated DNA. When cohesins
are inactivated, sister chromatids do not associate properly with each other.

11. M-CDKs
• Mitotic cyclins are synthesized during S phase and G2 and bind to CDK1.
• However, the cyclin-CDK complex is not active because threonine 14 and
tyrosine 15 of the CDK1 subunit are phosphorylated by the protein kinase Wee1.
• Once DNA replication has been completed, the protein phosphatase Cdc25 is
activated and dephosphorylates CDK1.
• Active mitotic CDKs further stimulate Cdc25.
• At the same time, mitotic CDKs inhibit Wee1, the protein kinase that places
the inhibitory phosphorylation on the CDK subunit.
• Ongoing DNA replication inhibits Cdc25 activity.

12. MITOTIC CDKs promote spindle formation
Mitotic CDKs induce nuclear envelope breakdown in most eukaryotes by phosphorylating
lamins.
• Centrosome duplication occurs during S phase.
• Mitotic CDKs induce the separation of the duplicated centrosomes, which initiates
mitotic spindle formation.
• Sister chromatids attach to the mitotic spindle via their kinetochores in a bi-oriented
manner, with one sister kinetochore attaching to microtubules emanating from one
spindle pole and the other one to microtubules nucleated by the other spindle pole.
• Cells sense bi-orientation of sister chromatids through a tension-based mechanism.
When kinetochores are not under tension, the protein kinase Aurora B phosphorylates
the microtubule-binding subunits of the kinetochore, which decreases their
microtubule binding affinity.
• Chromosomes must be compacted for segregation.
• Condensins, protein complexes that are related to cohesins, facilitate chromosome
condensation and are activated by mitotic CDKs.

13. COMPLETION OF MITOSIS
• Cleavage of cohesin by separase induces chromosome segregation during
anaphase.
• At the onset of anaphase, APC/C is directed by Cdc20 to ubiquitinylate securin,
which is subsequently degraded by proteasomes.
• The degradation of securin activates separase.
• Exit from mitosis is triggered by mitotic CDK inactivation mainly brought
about by mitotic cyclin degradation.
• Exit from mitosis requires the activity of protein phosphatases such as Cdc14
to remove mitotic phosphates from many different proteins, permitting
mitotic spindle disassembly, the decondensation of chromosomes, and the
reassembly of the nuclear envelope.