Cell Cycle: Prokaryotic & Eukaryotic

• The cell cycle is coordinated and controlled at multiple levels including time, position, environment, and damage.
• The heterodimer of cyclin and cyclin-dependent kinase drives the eukaryotic cell cycle.
• The prokaryotic cell cycle and the phases of the eukaryotic cell cycle are important aspects of cell division.
• The purpose of the cell cycle is to copy the genome and partition the copies equally between daughter cells in both unicellular and multicellular organisms.
• A multicellular organism can grow to adult size through the cell cycle.
• The cell cycle maintains the total cell number of an adult organism.
• Lost or damaged cells are replaced by the cell cycle.

Prokaryotic Cell Cycle and Binary Fission

• Prokaryotes divide by binary fission.
• DNA attaches to the cytoplasmic membrane.
• The cell enlarges and its DNA duplicates.
• A septum forms, dividing the cell.
• The cell divides in two, with DNA partitioned into each new cell, followed by cell separation.
• Two pathways coordinated in cell division are DNA replication and cytokinesis.

DNA Replication in Prokaryotes

• The circular chromosome of prokaryotes has one origin (ori) of replication.
• Two replication forks form at the origin, and replication is bidirectional.
• The result is two identical copies of the circular chromosome.

Cytokinesis in Prokaryotes

• An early step in bacterial cytokinesis is the formation of a ring of FtsZ protein on the inner surface of the cytoplasmic membrane at the division site.
• FtsZ is distributed randomly throughout the cell's cytoplasm.
• The FtsZ ring contracts, leading to cell division.
• In rapidly growing bacteria, the cell cycle is shorter than the time needed to copy DNA.
• Cell division takes 20 minutes, while DNA replication takes 40 minutes.
• DNA replication is initiated before completion of the previous round, which is called multifork replication.
• Mutifork replication ensures at least one round of replication finishes before cytokinesis.

Eukaryotic Cell Cycle: Additional Complexities

• The genome consists of multiple linear chromosomes, requiring coordinated replication and faithful segregation.
• Multicellularity involves cells functioning within organs and tissues.
• Numerous organelles must be partitioned into daughter cells.
• While details vary across organisms and life stages, some characteristics are universal.
• DNA must be faithfully replicated.
• Replicated chromosomes must be accurately segregated.

Phases of the Eukaryotic Cell Cycle

• G1 (Gap 1): The growth phase involves doubling the mass of organelles and protein, including synthesizing enzymes that drive DNA replication.
• S: DNA Synthesis phase, with chromosome duplication.
• At the end of the S phase, each replicated chromosome consists of a pair of identical sister chromatids.
• Cohesin ensures that sister chromatids do not drift apart to allow bipolar attachment to the mitotic spindle.
• G2: Preparation for mitosis, marked by two events.

Key Events in Mitosis

• Chromosome condensation occurs when condensin encircles loops of DNA and compresses the sister chromatids into a compact structure.
• Formation of the mitotic spindle involves the kinetochore attaching proteins to the centromere.
• Mitotic spindle: bipolar array of microtubules.
• Spindle pole bodies lie outside the nucleus; the nuclear membrane must break down early in mitosis for spindle access to chromosomes.
• Tension in the spindle pulls chromosomes, but sister chromatids are still held together by cohesin.
• The chromatids segregate when the kleisin subunit of cohesin is cleaved by a protease.

Cytokinesis in Eukaryotes

• Cytokinesis is the end of the cell cycle; it occurs once sister chromatids have reached opposite poles.
• The nuclear membrane begins to reform.
• The cytoplasm is divided in two by a contractile ring of actin and myosin II filaments, pinching the cell to give two daughters, each with one nucleus.
• In animal cells, the contractile ring divides the cytoplasm from the outside in.
• In plants, a contractile ring does not form; instead, a new cell wall is constructed between the daughter nuclei, partitioning the cytoplasm from the inside out.
• The phragmoplast guides new wall synthesis that contains microtubules derived from the mitotic spindle; Golgi-derived vesicles are transported along these microtubules.

Variations in the Cell Cycle

• Details of the cell cycle vary depending on the organism and time however faithful replication and segregation of chromosomes remain the same.
• Early embryonic cycles are divisions without growth; somatic cells maintain a constant size and cells grow after each division.
• Early embryonic cycles are 20 times faster than somatic cells.
• Multicellular organisms operate an open mitosis, where the nuclear envelope breaks down and reforms because the SPB is outside the nucleus.
• Unicellular organisms operate a closed mitosis where the nuclear envelope remains intact throughout.
• The spindle pole body (SPB) is the sole site of microtubule organization.
• The SPB is embedded in the nuclear envelope in baker's yeast (Saccharomyces cerevisiae).

Polarity in Cell Division

• In asymmetric cell division, daughter cells can differ in size/cytoplasmic content and develop along different pathways.
• Mother cells must segregate cell fate determinants to one side and position the division plane so one daughter inherits the determinants.
• P granule segregation occurs in the nematode worm development Caenorhabditis elegans.
• Stem cells are attached to niche cells, blocking differentiation but allowing cell division.
• One daughter cell is released to differentiate while the other remains attached to niche cells and remains a stem cell.

Cell Cycle Control

• Anchorage dependence is displayed by animal cells attached to a substratum in order to divide.
• Density-dependent inhibition occurs when cells stop dividing upon contact with each other (contact inhibition).
• Checkpoints include Cell Cycle Engine, Coordination and Checkpoints
• Cell cycle engine involves a protein complex that drives the cycle.
• Coordination ensures replicated DNA goes through mitosis before replication.
• Checkpoints ensure the cycle stops if the cell is deprived of nutrients, DNA is damaged, or chromosomes fail to attach to the spindle.

Cell Cycle Engine: Cyclin-Dependent Kinase(CDK)

• Phases of the cell cycle are driven by a protein kinase (CDK).
• Levels of the kinase remain constant throughout the cell cycle.
• Activity, not the levels, of the kinase activates phases of the cycle.
• The kinase becomes active, when complexed with cyclin.
• Cyclins are the regulators because they undergo synthesis and degradation cycles.
• Different CDK and cyclin pairs activate different phases of the cell cycle.
• G1/S phase cyclin (cyclin E) triggers the G1/S transition and commits the cell to the cycle, including commitment to DNA replication.
• M phase cyclin (cyclin B) promotes entry into mitosis, activates condensin, and induces nuclear membrane breakdown.
• Mitotic CDK phosphorylates nuclear lamin, causing depolymerization of lamin filaments and disintegration of the lamina mesh.
• CDK-cyclin complexes trigger different phases because cyclin directs the kinase to specific target proteins.
• Cyclins are degraded by proteolysis which terminates phases they control.
• Cyclin B degradation is required for exiting from mitosis and ending the cell cycle.

Coordination in Cell Division

• Phases are tightly regulated to occur in the proper order; S and M phases only happen once during each cycle.
• Mechanisms exist to prevent re-replication of G2 DNA.
• Fusing an S phase with a G1 phase cell, the G1 DNA is instructed to enter the S phase.
• Fusing an S phase with a G2 phase cell, the G2 is not forced into the S phase.

Cell Cycle Checkpoints

• Surveillance mechanisms continually ensure the next phase is not initiated unless the previous one has been completed.
• G1 checkpoint involves the restriction point (R) where a positive signal (growth factor) from the outside triggers cell division.
• G2/M checkpoint confirms if DNA synthesis has completed which enables the cell cycle to be suspended if there is less DNA passed to progeny.
• The spindle checkpoint ensures each chromosome is attached to the spindle which would be suspended if they were not attached.
• The DNA damage checkpoint operates throughout the cycle and arrests the cycle while damage is repaired.

Consequences of Checkpoint Failure

• In the case of DNA damage checkpoint failure, the cell cycle keeps turning despite DNA damage, leading to mutations and cancer.
• In the case of spindle checkpoint failure, unequal segregation of chromosomes would occur and lead to human aneuploidies.
• An example of spindle checkpoint failure is Down’s Syndrome, which is caused by an extra copy of chromosome 21.
• All cancers feature a deregulated cell cycle (as a consequence of mutation).
• Cancer signals start and stop which ignore signals, damage of the genome, and leads to no communication with other cells.
• In the prokaryotic cell cycle, multifork replication compensates for the mismatch in timing between DNA replication and cell division.
• The eukaryotic cell cycle, which is divided into four phases, enables faithful replication and segregation of chromosomes.
• The cyclin-dependent kinase/cyclin complex drives the eukaryotic cell cycle.
• Checkpoints involved in the cell cycle help guard against the accumulation of mutations and mis-segregation of chromosomes.