Cell cycle

THE GENETIC BASIS OF CELL CYCLE

CELL CYCLE

• All multicellular organisms originate from the mitotic division of single fertilized egg.

• Division of cell into daughter cells takes place through cell cycle under controlled way.

• Cell cycle is the cyclic series of steps controlled by specific set of genes and genes products in order to reduce chances of error during division cycle.These are called “Cell Divison Cycle genes” or cdc genes.

Phases of cell cycle

• It consists of 2 major phases:– Inter phase :• G1 (pre-synthetic phase) : longest.• S (DNA synthesis) :long.• G2 (pre-mitotic phase): shorter.

– Cell division (mitotic phase) : shortest Karyokinesis.(nuclear division) Cytokineisis.(cytoplasmic division)

Forces controlling cell cycle

• Who told the cell that”let’s start division”?• Obviously “Molecular signals” in the form of

gene expression would tell the cell to jump from one phase to next.

• But if DNA is mutated,damage or injuried checkpoints would never let the cell enter in S phase from G 1 phase untill repair does not occur.If no repair cell would commit suicide.

Checkpoints

• Originality of DNA is checked at checkpoints.• G1-S Checkpoint:Only repaired DNA can pass

through this checkpoint and can enter into S Phase otherwise get arrested.

• G2-M Checkpoint: G2 checkpoint would ensure any error during DNA replication in S phase.If any chromosomal part is missing,cell would be arrested for repair.

• M Checkpoint: allignment of chromosome is checked.Anaphase chromosome checking.

Positive & Negative affects of gene expression during G 1 Phase

• Some group of genes activate other genes group and they have positive coordinated function.e.g. Genes products activating DNA replication.While some inhibit these genes expression as those cells in G 0.

• It means DNA replication inhibiting genes(brakes) are over working and DNA replication activating genes(acceleraters) are underworking.

How +ve affect is produced during G1?

• Genes products produced by diploid cell:• One group of genes produce proteins which move

out of cell called Growth Factors.• Second group produce product which is inserted into

membrane of the same cell called Receptors for GF.• Third group of genes would form product which

send signals to nucleus from receptor called Signal Transducer proteins.

• STP would activate Responder proteins which form transcriptional factor.

• TF act on special genes and form specific molecules called Cycline.It is activated only when cell has to do replication.But Cyclin-Dependent Kinase(CDKs) remain always in cell but inactive which work only in the presence of cyclin.

• Now cyclin would make complex with CDKs.And become enzymatically active.

• This complex would phosphorylate Retinoblastema Proteins (Rb) which has “Molecular Key(E2F)”.After phosphorylation this key would be release and bind with genes which move the cell to S Phase for replication.

• Diifferent GF form dimer and send same signals to RB to form TF.

• All above mentioned genes are called “Protoncogenes”. Defects in theses genes cause cancer.

G0 phase :

It is the resting phase.In these cells cyclin D is in decreased

concentration.Rb protein is in hypo-phosphorylated it means

less phosphoryation (active form).Hence, holds the cell cycle at check point 1 by

inhibiting the expression of several transcription proteins(E2F) that codes cyclins A and E necessary for cycle progression.

Growth factor stimulation takes the G0 cells to G1 phase.

S phase :

Cyclin E/cdk and cyclin A/cdk regulate the processes in phase S.

By phosphorylating and activating proteins and enzymes that are involved in DNA synthesis.

G2 check point : located at the end of G2 phase trigerring onset mitosis after ensuring cell Is ready for mitosis. The entry into mitosis is initiated by Maturtion promoting factor (MPF).which contans cdc25 an activting phosphatase which removes inhibitory phosphates within the complex to facilitates transition to the next step.Cdc25 is inactivated in case of syntheis of faulty gene during Sphase.

M phase (mitosis):

Mitosis is the distribution of the two sets of chromosomes into two separate and equal nuclei.

It consists of four stages• prophase,• metaphase,• anaphase,• Telophase• After M Phase Cytokinesis takes place and parent

cell divide into 2 daughter cells.

Positive regulators :

• Are those which control the changes necessary for cell cycle to continue & determine a cell's progress through the cell cycle. They are pro mitotic.

• They include:-– Cyclins– Cyclin-dependent kinases(cdks)

Different cyclin-CDK combinations determine the downstream proteins targeted .

Cyclin A activtes cdk 1&2 , cyclin B activates cdk1, cyclin D activates cdk4 & 6,(Phosphorylate RB proteins)cyclin E activates cdk2. (Push cell from G1 To S Phase)there are abt 8 different cyclins.

Negative regulators

• These oppose the positive regultors i.e they are anti mitotic.

• An optimum balance between the two ensures a normal cell cycle.

• Over expression of positive regulators results in unchecked cell division(cancer).ATP no coversion to ADP.

• Over expression of negative regulators results in cessation of cell division.

Different types of Negative regulators :

–Rb ( Retinoblastoma)proteins.

–P53 gene

Rb (retinoblastoma) proteins :which bind to transcription factor & inhibit syntheis of vital proteins required for cell cycle.Rb proteins act at G1 - S (pre-synthetic phase) .

Rb proteins get inactivated upon phosporylation (cyclin-cdk dimer) &are active in the un phosphorylated form.

P53 gene ( guardian of genome) :codes for P53 protein whose conc in normal cells is very low but increases upon DNA damage.

Figure 12.14

Control system

G2 checkpoint

M checkpoint

G1 checkpoint

G1

S

G2M

THE END