The document summarizes the key phases and checkpoints of the cell cycle, as well as the roles of cyclins and cyclin-dependent kinases (CDKs) in regulating progression through the cell cycle. It notes that the cell cycle consists of M (mitosis), G1, S (DNA synthesis), and G2 phases, with checkpoints to detect errors and damage. Cyclins activate CDKs to phosphorylate proteins and drive progression, with Cyclin D activating CDK4/6 to promote G1/S transition, Cyclin E and A activating CDK2 to initiate DNA synthesis, and Cyclin B activating CDK1 for G2/M transition. The Rb protein also regulates the G1 checkpoint

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CELLCYCLE
(DNA REPLICATION)

2. Phasesofcellcycle
• M- mitotic phase
• G1 - gap 1 phase
• S - synthetic phase ( replication of DNA )
• G2 - gap 2 phase
• Replication of DNA genome occurs only at a speci
fi
ed time - S phase
• NOTE - When the cell is not growing, it exists in a dormant or undividing phase (G0) .
4 distinct ph
a
ses

3. CHECKPOINTS
• M phase - Detection of improper spindle
• G1 phase - Damaged DNA detected
• S phase - Detection of incomplete replication
• G2 phase - Detection of damaged DNA
• Note : If any damage to DNA is detected, the cell cycle will not progress until appropriately
corrected . If not possible to repair the damage done, cells undergo apoptosis
(programmed cell death) .

4. CYCLINS
• Associated with the transition of one phase of cell cycle to another
• synthesized throughout the cell cycle, and are abruptly destroyed
during mitosis.
• Concentration of cyclins increase or decrease during course of cell
• Cyclins activate CDKs which phosphorylate speci
fi
c substrates
(regulatory proteins)
Cyclin A, B, D
a
nd E

5. CyclinsandCyclin-DependentKinases
InvolvedinCell-CycleProgression
Cyclin Kinase Function
D CDK4, CDK6
Progression past restriction
point at G,/S boundary
E, A CDK2
Initiation of DNA synthesis
in early S phase
B CDK1 Transition from G, to M

6. CyclinD
• activate CDK4 and CDK6.
• Cyclin D levels rise in late G phase
• It allow progression beyond the start (yeast) or restriction point
(mammals), the point beyond which cells irrevocably proceed into
the S or DNA synthesis phase
Cyclin D1 is
a
n essenti
a
l regul
a
tor of the G1–S tr
a
nsition

7. • Retino-blastoma protein inhibits cell cycle at G1 check point thus ,
replication .
• Body circumvents this block by phosphorylation of Rb protein.
• This is done normally by cyclin D-CDK.
• Note : Tumor antigens will attach with Rb protein, so Rb
inhibition is lost; there will be uncontrolled cell division, leading to
cancer
Retinobl
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(RB) Oncosuppressor Protein

8. • The D cyclins activate CDK4 and CDK6.
• These two kinases are also synthesized during G1 in cells undergoing active division.
• The D cyclins and CDK4 and CDK6 are nuclear proteins that assemble as a complex in
late G1 phase.
• The cyclin-CDK complex is now an active serine-threonine protein kinase.
• One substrate for this kinase is the retinoblastoma (Rb) protein.
• Rb is a cell-cycle regulator because it binds to and inactivates a transcription factor
(E2F) necessary for the transcription of certain genes (histone genes, DNA replication
proteins, etc.) needed for progression from G, to S phase.
• The phosphorylation of Rb by CDK4 or CDK6 results in the release of E2F from Rb-
mediated transcription repression—thus, gene transcription activation ensues and cell-
cycle progression takes place.

10. CyclinEandA
• Activates CDK2
• Cyclin E and CDK2 form a complex in late G1
• Cyclin E is rapidly degraded, and the released CDK2 then forms a
complex with cyclin A.
• This sequence is necessary for the initiation of DNA synthesis in S
phase

11. CyclinB
• A complex between cyclin B and CDK1
is rate-limiting for the G2,/M transition
in eukaryotic cells.

12. Sphase
• Mammalian cells contain greater quantities of DNA polymerase than during the
nonsynthetic phases of the cell cycle.
• Furthermore, those enzymes responsible for formation of the substrates for DNA
synthesis—that is, deoxyribonucleoside triphosphates—are also increased in activity
• During the S phase, the nuclear DNA is completely replicated once and only once.
• LICENSING :
• After chromatin has been replicated, it is marked so as to prevent its further replication
until it again passes through mitosis.
• This process is termed replication licensing.

13. • The molecular mechanisms for this phenomenon in human cells involve
dissociation and/or cyclin-CDK phosphorylation and subsequent degradation of
several origin binding proteins that play critical roles in replication complex
formation.
• Consequently, origins
fi
re only once per cell cycle.
• In general, a given pair of chromosomes will replicate simultaneously and within a
fi
xed portion of the S phase on every replication.
• On a chromosome, clusters of replication units replicate coordinately.
• The nature of the signals that regulate DNA synthesis at these levels is unknown, but
the regulation does appear to be an intrinsic property of each individual
chromosome that is mediated by the several replication origins contained therein.