Cell cycle

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Overview of the Cell Cycle and Its Control
CHECKPOINTS
In vertebrates and diploid yeasts, cells in G1 have a diploid number of
chromosomes (2n), one inherited from each parent. In haploid yeasts,
cells in G1 have one of each chromosome (1n).

Rapidly replicating human cells progress through the full cell cycle
in about 24 hours: mitosis takes ≈30 minutes; G1, 9 hours; the S
phase, 10 hours; and G2, 4.5 hours.
only ≈90 minutes in rapidly growing yeast cells.

Postmitotic cells in multicellular organisms can "exit" the cell cycle and
remain for days, weeks, or in some cases (e.g., nerve cells and cells of
the eye lens) even the lifetime of the organism without proliferating
further. Most postmitotic cells in vertebrates exit the cell cycle in G1,
entering a phase called G0.

G0 cells returning to the cell cycle enter into the S phase; this reentry is
regulated, thereby providing control of cell proliferation
The master controllers of these events are a small number of
heterodimeric protein kinases that contain a regulatory
subunit and catalytic subunit.

These kinases regulate the activities of multiple proteins involved

in DNA replication and mitosis by phosphorylating them at
specific regulatory sites, activating some and inhibiting others to
coordinate their activities.
Regulation of CDK Activity

Three key features of these kinases

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Cyclins and CDKs: Nomenclature and Their Roles in the
Mammalian Cell Cycle

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 An overview of how CDKs regulate cell cycle
progression.

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 Structural models of human CDK2

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Cyclins Determine the Activity of CDKs

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 Regulation of Cyclins level to appropriate
cell cycle stage

Transcriptional control of the cyclin subunits is one mechanism that ensures proper
temporal expression of the cyclin
But
Cyclins Levels Are Primarily Regulated by Protein Degradation. Such as G1/S
phase cyclin degradation by SCF (Skp1, Cullin, and F-box proteins) and S phase
and mitotic cyclins degradation by APC/C ubiquitin-protein ligases.

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 Regulators of Cyclin-CDK Activity

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Commitment to the Cell Cycle and DNA Replication

Cells Are Irreversibly Committed to Division at a Cell Cycle Point Called START in
yeast or the Restriction Point for mammalian cells

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 START

CDK cascade triggers entry into the cell cycle

G1 cyclin-CDK complexes stimulate the formation of G1/S phase cyclin-CDKs,
which then initiate bud formation, centrosome duplication, and DNA replication
In yeast, the G1 cyclin gene is called CLN3 and its mRNA is produced at a nearly
constant rate throughout the cell cycle but its translation is regulated in response
to nutrient levels; acting as linchpin between cell cycle entry and nutrients signals
CLN3 transcript contains a short upstream open reading frame that inhibits
translation initiation when nutrients are limited
In the presence of sufficient nutrients, the TOR signaling pathway, which senses
nutrients and growth factor signals, is active and stimulates translational activity
Once sufficient Cln3 is synthesized from its mRNA, Cln3-CDK complexes
phosphorylate and inactivate the transcriptional repressor of many key genes
required for cell cycle entry and subsequent steps.

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 Cell-Cycle Control in Mammalian Cells
In multicellular organisms, precise control of the cell cycle during development and
growth is critical for determining the size and shape of each tissue.
Cell replication is controlled by a complex network of signaling pathways that integrate
extracellular signals about the identity and numbers of neighboring cells and intracellular
cues about cell size and developmental program.

Most cells withdraw from the cell cycle during G1, entering the G0 state, to
differentiate.
Some differentiated cells (e.g., fibroblasts and lymphocytes) can be stimulated to reenter
the cycle and replicate.

Many differentiated cells, however, never reenter the cell cycle to replicate again; they
are referred to as postmitotic cells.
 Mammalian Restriction Point is Analogous to start in Yeast Cells

Most studies of mammalian cell-cycle control have been done with cultured cells that
require certain polypeptide growth factors (mitogens) to stimulate cell proliferation.

Mammalian cells cultured in the absence of growth factors are arrested with a diploid
complement of chromosomes in the G0 period of the cell cycle.
If growth factors are added to the culture medium, these quiescent cells pass through
the restriction point 14-16 hours later, enter the S phase 6-8 hours after that, and
traverse the remainder of the cell cycle.

Like START in yeast cells, the restriction point is the point in the cell cycle
at which mammalian cells become committed to entering the S phase and completing
the cell cycle.
If mammalian cells are moved from a medium containing growth factors to one lacking
growth factors before they have passed the restriction point, the cells do not enter the S
phase.
But once cells have passed the restriction point, they are committed to entering
the S phase and progressing through the entire cell cycle, which takes about 24
hours for most cultured mammalian cells.
Mitogen activate receptor tyrosine kinase- linked single transduction pathways which
leads to the activation of many genes.
These genes can be classified to early and delayed response genes
The transcription of early response genes is induced within a few minutes

Many of the early response genes encode transcription factors

The early response transcription factor Myc induces the transcription

of G1 cyclin and CDK genes

In addition to being controlled by transcription, G1 CDKs are regulated by CKIs

Mitogens can also inhibit the production of this CKI by inhibiting its transcription
Control of the G1–S phase transition

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 conclusion

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 Surveillance Mechanisms in Cell
Cycle Regulation (Checkpoint pathways)

Ensure that the next cell cycle event is not initiated until the previous one has been
completed, accurately
• Checkpoint pathways consist of
1. Sensors that monitor a particular cellular process and in response to the defect
activate
2. a signal transduction pathway that initiates the response
3. And an effector, activated by these signaling pathways, initiate repair and halts
cell cycle progression until the defect is corrected
The checkpoint pathway also induce apoptosis if the defect cannot be repaired
Events monitored by checkpoints pathways includes Growth, DNA replication, DNA
damage, kinetochore attachment to the mitotic spindle, and positioning of the
spindle within the cell

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 Surveillance Mechanisms in Cell
Cycle Regulation (Checkpoint pathways)

They function by controlling the protein kinase activities of the cyclin-CDKs through
a variety of mechanisms
1. Regulation of the synthesis and degradation of cyclins
2. Phosphorylation of CDKs at inhibitory sites
3. Regulation of the synthesis and stability of CDK inhibitors (CKIs)
4. And regulation of the APC/C ubiquitin-protein ligase.

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 The DNA Damage Response System Halts Cell
Cycle Progression When DNA Is Compromised

The incomplete replicated or unrepaired damaged DNA will leads

 mostly cell death
Or loss of control over cell growth and division and eventually cancer

Therefor, the cells harbor checkpoint mechanism to prevent these anomalies

The replication errors and environmental agents such as x- rays and UV light cause genetic
alteration/ damages

DNA damage exists in many different forms and degrees of severity

 Double strand break
 Single strand break
Structural changes in nucleotides
 DNA mismatches

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 The DNA Damage Response System

Cells detect these different types of damages and respond by activating repair
pathways and halting cell cycle progression
Cell cycle arrest can occur in G1, S phase, or G2
 in case of severe damage cells undergo apoptosis
 Central to these damages detection is a pair of similar proteins kinases called
ATM and ATR, which are recruited to the site of DNA dmage
They then sequentially recruits adapters proteins and additional kinases Chk1 and
Chk2
The later activates repair mechanism, arrest cell cycles or induce apoptosis
ATM recognize double stranded breaks and is recruited directly by MRN complex,
which binds to the broken ends
 The ATR is able to recognize more diverse types of DNA damage
 The ATR binds to and is activated by single stranded DNA

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 The DNA damage response system

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Overview of DNA damage checkpoint controls in the
cell cycle.

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