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Questions and Answers
What occurs during the G1 phase of the mammalian cell cycle?
What occurs during the G1 phase of the mammalian cell cycle?
What is the main purpose of the S phase in the cell cycle?
What is the main purpose of the S phase in the cell cycle?
Which phase follows the G2 phase in the cell cycle?
Which phase follows the G2 phase in the cell cycle?
What role do checkpoints serve in the cell cycle?
What role do checkpoints serve in the cell cycle?
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What happens if DNA damage is detected during the S phase?
What happens if DNA damage is detected during the S phase?
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What primarily defines cellular senescence?
What primarily defines cellular senescence?
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Which CDK inhibitors primarily inhibit cyclin D-CDK4/6 complexes?
Which CDK inhibitors primarily inhibit cyclin D-CDK4/6 complexes?
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What is the Hayflick limit?
What is the Hayflick limit?
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Which phase is associated with irreversible lack of cell division?
Which phase is associated with irreversible lack of cell division?
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What occurs to p21/p27 as more CDK4/6-cyclin D complexes form?
What occurs to p21/p27 as more CDK4/6-cyclin D complexes form?
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Which CDK complex is responsible for the hyper-phosphorylation of Rb as the cell cycle progresses past the restriction point?
Which CDK complex is responsible for the hyper-phosphorylation of Rb as the cell cycle progresses past the restriction point?
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What is the primary role of the Rb protein in the cell cycle?
What is the primary role of the Rb protein in the cell cycle?
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When does the restriction point in the cell cycle occur?
When does the restriction point in the cell cycle occur?
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Which of the following statements regarding mitogens is correct?
Which of the following statements regarding mitogens is correct?
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What happens to Rb as the cell cycle progresses past the restriction point?
What happens to Rb as the cell cycle progresses past the restriction point?
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What is a consequence of telomere shortening?
What is a consequence of telomere shortening?
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What structure is formed at the end of telomeres?
What structure is formed at the end of telomeres?
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What is TRF2 and its significance regarding telomeres?
What is TRF2 and its significance regarding telomeres?
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How much telomeric DNA is potentially lost in each cell division?
How much telomeric DNA is potentially lost in each cell division?
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What complex is responsible for protecting telomeric DNA from degradation?
What complex is responsible for protecting telomeric DNA from degradation?
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Study Notes
The Mammalian Cell Cycle
- The mammalian growth-division cycle is divided into four phases: G1, S, G2, and M.
- G1: The first growth period of the cell cycle, during interphase. The cell responds to its environment and synthesizes nucleotides and organelles.
- S: During this phase, DNA is replicated.
- G2: The second growth period of the cell cycle, rapid cell growth and protein synthesis occurs, preparing the cell for mitosis.
- M (Mitosis): Cell division.
Cell Cycle Checkpoints
- Checkpoints ensure a cell properly completes each phase before advancing to the next.
- DNA damage checkpoints: These mechanisms prevent entry into S phase if the genome is damaged, or halt DNA replication during S phase if damage is detected.
- Entrance into M phase is blocked if DNA replication is not complete.
- During mitosis, anaphase is blocked if chromatids are not correctly assembled on the mitotic spindle.
Cell Cycle Checkpoints (More details)
- The cell cycle has multiple checkpoints that monitor for unfavorable or damaged conditions.
- G1 checkpoint: Checks for unfavorable extracellular environment, damaged DNA (p53).
- G2 checkpoint: Checks for completely replicated DNA.
- G2/M checkpoint: Checks for damaged or incompletely replicated DNA.
- Mittic checkpoint: Checks if chromosomes are attached to the mitotic spindle correctly for accurate separation.
What Regulates Entry in Each Cell Cycle Phase?
- Different cyclin-dependent kinase (CDK) complexes regulate entry and exit from various cell cycle phases.
- The concentration of specific cyclins fluctuates throughout the cell cycle, regulating CDK activity.
The Cell Cycle as Governor of Growth and Proliferation
- Growth factor receptors, monitors of genome integrity, TGF-β receptors, integrins, and monitors of cell metabolism regulate the cell cycle.
- A cell can enter a quiescent state (G0) or progress into the active cell cycle based on various signals.
Restriction Point (R Point)
- Responsiveness to extracellular signals is only during a discrete window in G1, just before the end of G1.
- The restriction point (R) is where a cell commits to advancing through the cell cycle, staying in G1, or returning to G0 (quiescent state).
- Rb family plays a role in controlling the restriction point.
Cell Cycle Dependent Phosphorylation of Rb
- Rb is hypo-phosphorylated by CDK4/6 in early cell cycle stages.
- As the cell progresses through the R point, Rb becomes hyper-phosphorylated by CDK2.
- Exit from mitosis (M) causes protein phosphatase type 1 (PP1) removing phosphate groups fromRb.
Control of R Point by Mitogens
- Mitogens induce cell proliferation and regulate cell cycle entry.
- Restriction points are regulated by Rb phosphorylation, not expression, by CDKs.
E2F and Rb Interaction
- Rb binds to E2F, inhibiting its transcription activating domains and repressing transcription.
- After the R point, Rb is hyper-phosphorylated, releasing E2Fs, and allowing the transcription of late G1 genes.
- During S phase, E2Fs are inactivated and/or degraded.
CDK Inhibitors (CDKI)
- CDKs are inhibited by various CDKIs at various stages of the cell cycle.
- p16, p15, p18, and p19 inhibit cyclin D-CDK4/6 complexes, active in early and mid G1.
- p57, p27, and p21 inhibit remaining complexes throughout the cycle.
- p21 and p27 can stimulate CDK4/6 while inhibiting CDK2.
Senescence
- Senescence is an irreversible growth arrest where cells are metabolically alive but unable to proliferate further.
- Cells can reach a limit in the cell division capabilities called the Hayflick limit.
The Hayflick Limit
- Cells have a limited capacity for cell division in culture.
- A certain number of divisions before senescence occurs (growth stops).
- Normal cells in culture can only divide a fixed number of times before stopping division.
Telomeres
- Telomeres are repetitive nucleotide sequences at the ends of linear chromosomes.
- Telomere shortening causes end-to-end fusions, karyotype chaos, and widespread death by apoptosis.
- Telomere shortening plays a crucial role regulating cell division.
Telomeres structure
- Telomeres are G-rich sequences.
- Repeats average 5-10 kilobases in humans.
- Telomeres consist of double-stranded DNA including a G-rich strand and C-rich strand.
- A single-stranded 3' overhang is part of the G-rich strand.
- Telomeres form a T-loop structure protected by protein complexes.
Telomeres - protein complexes
- Telomeric DNA is protected from degradation by a group of physically associated proteins called the shelterin complex.
- The shelterin complex includes proteins such as TRF1, TRF2, POT1, and TIN2.
Telomere end replication problem
- Ineffective copying of chromosome ends during S phase.
- RNA primers initiate lagging strand synthesis.
- Exonucleases can erode telomeres.
- Telomeres lose 50-100 base pairs of DNA with each cell division.
Telomere shortening
- With each cell division, telomeric DNA shortens.
- Telomeres shorten from 10-15kb to 3-5kb after 50-60 cell divisions.
- Telomere shortening leads to a cellular crisis, where cells undergo irreversible growth arrest.
Telomeres and DNA damage
- Unprotected chromosome ends can fuse and cause DNA damage.
- Non-homologous chromosome fusions lead to more DNA damage and subsequent cellular changes.
How can Telomere shortening be prevented?
- Telomerase prevents telomere shortening.
Telomerase
- Telomerase (TERT) is a reverse transcriptase that adds new telomeric DNA repeats.
- Uses its own RNA template to synthesize telomeres.
- Essential for maintaining telomere length.
Telomerase and Cancer
- Cancer cells often escape crisis by expressing telomerase.
- The presence of telomerase in cancer cell samples is high.
- Expression of hTERT (human telomerase reverse transcriptase) is crucial in immortalizing cells.
Telomeres, Aging, and Disease
- Short telomeres are associated with aging.
- Short telomeres are biomarkers for cellular aging.
- Short telomeres can lead to cardiovascular disease.
- Telomerase activity is linked to disease, impaired cellular function, and weakened immune function.
- Dyskeratosis congenital is a genetic disorder from telomerase defects.
Mitosis
- Mitosis serves functions such as growth, tissue repair, and asexual reproduction in single-celled organisms.
- Daughter cells are genetically identical to the parent cell.
- Mitosis involves the following phases: Prophase, Metaphase, Anaphase, Telophase & Cytokinesis.
Meiosis
- Meiosis produces gametes.
- Meiosis involves two sequential stages: Meiosis I and Meiosis II.
- Prophase I: Homologous chromosomes pair and exchange segments (crossing over) via chiasmata
- Meiosis I: Reduces the chromosome number by half.
- Meiosis II: Resembles mitosis, leading to genetically unique haploid cells.
- Important for promoting genetic diversity in sexual reproduction.
Metaphase Chromosomes
- During mitosis, chromosomes align at the cell equator.
- The chromatin is highly condensed.
- Sister chromatids are held together at the centromere.
Genetic Cross-over
- Homologous chromosomes exchange genetic material during synapsis of meiosis I.
- This leads to genetic variation in gametes.
- Chiasma represent points where crossing over has occurred.
Conclusion
- The cell cycle is strictly controlled by checkpoints.
- Cyclin-dependent kinases (CDKs) and cyclins play a key role.
- Retinoblastoma (Rb) is a tumor suppressor that controls progression through the restriction point.
- Telomeres protect chromosome ends and must be maintained by telomerase for cells to replicate.
- Mitosis and meiosis produce different cell types with varying genetic content.
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Description
This quiz covers the phases of the mammalian cell cycle, including G1, S, G2, and M stages. Additionally, it explores the critical checkpoints that regulate the progression through these phases. Test your understanding of how cells manage growth, DNA replication, and division.
