Cell Cycle

Objectives• List the four phases of cell cycle.• Define checkpoints in cell cycle and mention their

importance.• Define cyclins and cyclin-dependent kinases. • List their main types and describe their action as

positive regulators for cell cycle.

References:

Harper’s Illustrated Biochemistry, 26th edition, section IV; chapter 36 (DNA organization, replication & repair) pages:333-335 & page 339.

The Cell Cycle The series of events that take place in a cell leading to its division and duplication (replication) that produces two daughter cells.

The cell cycle has 4 phases:• G1: Gap 1• S: Synthetic• G2: Gap 2• M: Mitosis

Interphase• Before a cell can enter cell division, it needs to take in

nutrients. All of the preparations are done during interphase.

• Interphase is a series of changes that takes place in a newly formed cell and its nucleus, before it becomes capable of division again. It is also called preparatory phase or intermitosis. Previously it was called resting stage because there is no apparent activity related to cell division.

• Typically interphase lasts for at least 90% of the total time required for the cell cycle.

• Interphase proceeds in three stages, G1, S, and G2, preceded by the previous cycle of mitosis and cytokinesis.

• The cells nuclear chromosomes are duplicated during S phase.

G1 Phase• The first phase within interphase, from the end of the previous M phase

until the beginning of DNA synthesis, is called G1 (G indicating gap). It is also called the growth phase.

• During this phase the biosynthetic activities of the cell, which are considerably slowed down during M phase, resume at a high rate.

• The duration of G1 is highly variable, even among different cells of the same species.

• In this phase, cell increases its supply of proteins, increases the number of organelles (such as mitochondria, ribosomes), and grows in size.

• G2 phase :

Is a period of rapid cell growth and protein synthesis during which the cell readies itself for mitosis

G0 phase • The G0 is a period in the cell cycle in which cell exist in a quiescent

( inactive ) state .

• G0 phase is viewed as either an extended G1 phase where the cell neither dividing or preparing to divide or a distinct quiescent stage that occurs outside of the cell cycle.

• G0 is sometimes referred to as a “post-mitotic state “ since cell in G0 are in a non-dividing phase outside of the cell cycle .

• Some type of cell such as nerve and heart muscle cell become post-mitotic state when they reach maturity (i.e when they are terminally differentiated ) but continue to perform their main function for the rest of the organism’s life .

S Phase

• The ensuring S phase starts when DNA replication commences; when it is complete, all of the chromosomes have been replicated,

• The amount of DNA in the cell has effectively doubled.

Mitosis (M phase, mitotic phase)

• It is a relatively short period of the cell cycle.

• M phase is complex and highly regulated.

• The sequence of events is divided into phases, these phases are sequentially known as:

• prophase,

• metaphase,

• anaphase,

• telophase

• cytokinesis (strictly speaking, cytokinesis is not part of mitosis but is an event that directly follows mitosis in which cytoplasm is divided into two daughter cells)

Regulator of cell cycle

• Cyclins : • Rhythmic fluctuations in the abundance and activity of control

molecules pace the cell cycle.

• Cyclins are family of proteins whose concentration increase and decrease through the cell cycle.

• Cyclin Dependent Kinases (CDKs):

• Some molecules are protein kinases that activate or deactivate other proteins by phosphorylating them.

• The levels of these kinases are present in constant amounts, but these kinases require a second protein, a cyclin, to become activated.

• The complex of kinases and cyclin forms cyclin-dependent kinases (Cdks).

Cycling Dependent Kinases Regulate the Cell Cycle

Cyclins and cyclin-dependent kinasesinvolved in cell cycle progression.

Cyclin D:Activates CDK4, CDK6 which are

needed for Progression past restriction point at G1/S boundary.

Cyclin E, A:Activate CDK2 which is needed for

Initiation of DNA synthesis in early S phase.

Cyclin B:Activates CDK1 which is needed for

Transition from G2 to M.

Cell Cycle CheckpointsA number of surveillance systems control the cell cycle and interrupt its progression when DNA damage occurs or when the cells have failed to complete a necessary event.

Major Checkpoint Monitoring Molecules

• p53

• RB ( Retinoblastoma).

Checkpoint molecules are needed to mediate the cellular response to DNA damage.

That response range from cell cycle delay to allow time for DNA repair, to cell cycle arrest, to apoptosis.

p53P53: protein of molecular weight 53 Kda, suppresses cell replication and growth when there is DNA damage:

•DNA damage activates p53.

•P53 causes expression of p21.

•P21 is CDK-cyclin inhibitor (CKI).

•Inhibition of CDK halt progression through cell cycle.

P53 can also trigger apoptosis especially in response to radiation.

P53 is one of the most commonly mutated genes in human cancer

Apoptosis

Programmed cell death

RBRetinoblastom

• 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 G1 to S phase.

• The phosphorylation of Rb by CDK4 or CDK6 results in the release of E2F from Rb-mediated transcription repression—thus, gene activation ensures and cell cycle progression takes place.

Loss of RB

– Enables continuous DNA synthesis

– Found in melanoma and liposarcoma