The Eukaryo,c Cell Cycle

• The cell cycle of most cells consists of four coordinated processes:

1. cell growth,
2. DNA replica,on,
3. distribu,on of the duplicated chromosomes to daughter cells, and
4. cell division.

• In bacteria, cell growth and DNA replica,on take place throughout the cell cycle, and
duplicated chromosomes are distributed to daughter cells in associa,on with the
plasma membrane.

• In eukaryotes, however, the cell cycle is more complex and consists of four discrete
phases.
Phases of the Cell Cycle

• A typical eukaryo,c cell divide approximately every 24 hours.

• As viewed in the microscope, the cell cycle is divided into two basic parts: mitosis
and interphase.

• Mitosis (nuclear division) corresponds to the separa,on of daughter chromosomes

and usually ending with cell division (cytokinesis).

• However, mitosis and cytokinesis last only about an hour, so approximately 95% of
the cell cycle is spent in interphase -the period between mitoses.

• During interphase, the chromosomes are decondensed and distributed throughout

the nucleus, so the nucleus appears morphologically uniform.

• During Interphase both cell growth and DNA replica,on occur in an orderly manner
in prepara,on for cell division.
• In interphase, most dividing cells doubling in size between one mitosis and the
next.

• DNA is synthesized during only a por,on of interphase. The ,ming of DNA

synthesis thus divides the cycle of eukaryo,c cells into four discrete phases

- The M phase of the cycle corresponds to mitosis, which is usually followed by

cytokinesis.

• This phase is followed by G1 phase (gap 1), which corresponds to the interval (gap)
between mitosis and ini,a,on of DNA replica,on.

• During G1 the cell is metabolically ac,ve and con,nuously grows

• G1 is followed by S phase (synthesis) during which DNA replica,on takes place.

• The comple,on of DNA synthesis is followed by the G2 phase (gap 2) during which
cell growth con,nues and proteins are synthesized in prepara,on for mitosis.
 • The dura,on of these cell cycle phases varies considerably in different kinds of
cells.

• For a typical rapidly prolifera,ng human cell with a total cycle ,me of 24 hours,
the
- G1 phase might last about 11 hours, S phase about 8 hours,
- G2 about 4 hours, and M about 1 hour.

• Budding yeasts, can progress through all four stages of the cell cycle in only about
90 minutes.

• Even shorter cell cycles (30 minutes or less) occur in early embryo cells shortly
aYer fer,liza,on of the egg.

• In thjs case, however, cell growth does not

take place. Instead, these early embryonic
cell cycles rapidly divide the egg cytoplasm
into smaller cells.

• There is no G1 or G2 phase, and DNA

replica,on occurs very rapidly in these
early embryonic cell cycles, which
therefore consist of very short S phases
alterna,ng with M phases.
• some cells in adult animals cease division altogether (e.g., nerve cells)

• Analysis of the cell cycle requires iden,fica,on of cells at the different stages
discussed above.

• Although mito,c cells can be dis,nguished microscopically, cells in other phases of

the cycle (G1, S, and G2) must be iden,fied by biochemical criteria.

• Cells in S phase can be readily iden,fied because they incorporate radioac,ve

thymidine, which is used exclusively for DNA synthesis
• Cells at different stages of the cell cycle can also be dis,nguished by their DNA
content.

• For example, animal cells in G1 are diploid (containing two copies of each
chromosome), so their DNA content is referred to as 2n (n designates the haploid
DNA content of the genome).

• During S phase, replica,on increases the DNA content of the cell from 2n to 4n, so
cells in S phase have DNA contents ranging from 2n to 4n.

• DNA content then remains at 4n for cells in G2 and M, decreasing to 2n aYer

cytokinesis.

• Experimentally, cellular DNA content can be determined by incuba,on of cells

with a fluorescent dye that binds to DNA, followed by analysis of the fluorescence
intensity of individual cells in a fluorescence-ac,vated cell sorter.
Cell Cycle Checkpoints

• The events that take place during different stages of the cell cycle must be
coordinated with one another so that they occur in the appropriate order.

• For example, it is cri,cally important that the cell not begin mitosis un,l replica,on
of the genome has been completed.

• In most cells, this coordina,on between different phases of the cell cycle is
dependent on a series of cell cycle checkpoints that prevent entry into the next
phase of the cell cycle un,l the events of the preceding phase have been
completed.

• Several cell cycle checkpoints func,on to ensure that incomplete or damaged

chromosomes are not replicated and passed on to daughter cells
• These checkpoints sense unreplicated or damaged DNA and coordinate further cell
cycle progression with the comple,on of DNA replica,on or repair.

• For example, the checkpoint in G2 prevents the ini,a,on of mitosis un,l DNA
replica,on is completed.

• This G2 checkpoint senses unreplicated DNA, which generates a signal that leads to
cell cycle arrest.

• In addi,on to sensing unreplicated DNA, the G2 checkpoint senses DNA damage,

such as that resul,ng from irradia,on.

• If DNA damage is detected, arrest at the check-point allows ,me for the damage to
be repaired, rather than being passed on to daughter cells.
• DNA damage not only arrests the cell cycle in G2 but also at checkpoints in G1 and S
phase.

• Arrest at the G1 checkpoint allows repair of the damage to take place before the cell
enters S phase, where the damaged DNA would be replicated.

• The S phase checkpoint provides con,nual monitoring of the integrity of DNA to

ensure that damaged DNA is repaired before it is replicated.

• In addi,on, the S phase checkpoint provides a quality control monitor to promote

the repair of any errors that occur during DNA replica,on, such as the incorpora,on
of incorrect bases or incomplete replica,on of segments of DNA.

• Cell cycle arrest at the G1, S, and G2 checkpoints is mediated by two related protein
kinases, designated ATM and ATR, that recognize damaged or unreplicated DNA and
are ac,vated in response to DNA damage.

• ATM and ATR then ac,vate a signaling pathway that leads not only to cell cycle
arrest, but also to the ac,va,on of DNA repair and, in some cases, programmed cell
death.
• Muta,ons in the gene encoding ATM are responsible for the disease ataxia
telangiectasia, which results in defects in the nervous and immune systems as well
as a high frequency of cancer in affected individuals.

• Another important cell cycle checkpoint that maintains the integrity of the genome
occurs toward the end of mitosis.

• This checkpoint, called the spindle assembly checkpoint, monitors the alignment of
chromosomes on the mito,c spindle, thus ensuring that a complete set of
chromosomes is distributed accurately to the daughter cells.

• The failure of one or more chromosomes to align properly on the spindle causes
mitosis to arrest at metaphase, prior to the segrega,on of the newly replicated
chromosomes to daughter nuclei.

• As a result of the spindle assembly checkpoint, the chromosomes do not separate

un,l a complete complement of chromosomes has been organized for distribu,on
to each daughter cell.