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A briefe history of the cell cycle • 18xx Interphase-Mitosis • 1951 Discovery of a distinct S-phase • 1970 Cell fusion experiments • 1971 Discovery of MPF • 197x Yeast cdc mutants • 1983 Discovery of the first cyclins • 1988 Cyclin B+cdc2 = MPF • 199x Ubiquitin and the cell cycle • 1999 Sister chromatid separation

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Page 1: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

A briefe history of the cell cycle

• 18xx Interphase-Mitosis

• 1951 Discovery of a distinct S-phase

• 1970 Cell fusion experiments

• 1971 Discovery of MPF

• 197x Yeast cdc mutants

• 1983 Discovery of the first cyclins

• 1988 Cyclin B+cdc2 = MPF

• 199x Ubiquitin and the cell cycle

• 1999 Sister chromatid separation

Page 2: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

The most important role of cell cycle control is to ensure accurate chromosome segregation

M

G1

S

G2

Page 3: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

General principles and methods

G1 - To cycle or not to cycle

S- Replicating the genome

M-Segregating the genome

Cytokinesis - Making two cells

Page 4: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

ONCE and ONLY ONCE

Page 5: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Rao and Johnson 1970

Page 6: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Fluorescent Activated Cell Scan/Sorter (FACS)

Page 7: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

A typical FACS analysis

Page 8: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Methods for cell synchronisation

Page 9: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Model organisms I - Budding yeast (S.cerevisiae)

L. Hartwell

Page 10: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Model organisms II - Fission yeast (S.pombe)

P. Nurse

Page 11: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Identification of cell cycle ts mutants

Page 12: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 13: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Generation of temperature sensitive budding yeast mutants

Page 14: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Analysis of ts cell cycle mutants

G1S

M MM M

Page 15: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Maturation promoting factor

Page 16: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 17: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Oscillations of MPF

Page 18: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 19: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 20: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Somatic cell cycle Embryonal cell cycle

protein levels

phasecheckpoint

M S

START

S

START

M

Levels of Cyclin B oscillate during the cell cycle

0 1 10 12 14 16 205 8

Cyclin B1

Cyclin B2

S G2 M G1 S G2 M

STARTSTART M→A

65' 70' 75' 80' 85' 90' 95 100

M→ A M→ AM→ A

Page 21: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 22: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Cyclins and cyclin dependent kinases (cdks) - in Budding yeast

Cdk1 (cdc28)(S.p. cdc2)

Cln1,2,3G1

Clb5,6S

Clb3,4G2

Clb1,2

M

Page 23: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Cyclins and cyclin dependent kinases (cdks) - in multi-cellular organisms

Cdk1(S.p. cdc2)

Cyclin D1,2,3G1

Cyclin ECyclin A

S

Cdk4,6

Cdk2

Cyclin ACyclin B1,2,3

M

Page 24: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Cdc2/28 (=cdk1) is regulated by:

1. Binding of a cyclin2. Inhibitory phosphorylation3. Activating phosophorylation4. Binding of CKI5. Cellular localization

Page 25: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Synthesis(transcription and translation)

On OffPhosphorylationDephosphorylationDestruction

Methods of cellular regulation

Page 26: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 27: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

G1 - To cycle or not to cycle

S- Replicating the genome

M-Segregating the genome

Cytokinesis - Making two cells

Page 28: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 29: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 30: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

P

Cyc D

cdk4

pRB

E2F

E2FE2F

E2F P

PP

P

E2FE2FE2FE2F

Cyc E

cdk2

Page 31: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 32: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

G1 - To cycle or not to cycle

S- Replicating the genome

M-Segregating the genome

Cytokinesis - Making two cells

Page 33: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

The human genome is encoded by 3,000,000,000 bp (3x109) which must all be replicated within a few hours with the highest fidelity. The loss of a bp is irreversible and a single mistake could potentially lead to the death of the organism.

Page 34: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Analogy

One page contains about 3000 letters.

Imagine that you have to copy one million pages in a few hours and have to bind them into 23 volumes. You can use as many typist as you like but you are allowed no mistakes -no missing letter, no letter twice, and no substitutions.

Page 35: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 36: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 37: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

G1 - To cycle or not to cycle

S- Replicating the genome

M-Segregating the genome

Cytokinesis - Making two cells

Page 38: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 39: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 40: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

The story of the two blind men

• Two blind men go into a shop and buy each five different pairs of socks. Unfortunately all ten pairs were packed in the same bag.

• How can the two men separate the socks so that each of them will get five pairs ?

Page 41: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

The three factors that enable sister chromatid separation

• The glue - cohesins

• The pulling force - the mitotic spindle

• The timing mechanism - spindle checkpoint

Page 42: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

The three factors that enable sister chromatid separation

• The glue - cohesins

• The pulling force - the mitotic spindle

• The timing mechanism - spindle checkpoint

Page 43: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 44: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Sister chromatid separation from prometaphase to anaphase

Securin

Separase

Cohesin

metaphase

Securin

Separase

Cohesin

prometaphase

APC

Check

point

Separase

APC

Securin

Separase

anaphase

Check

point

Page 45: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Non-degradable securin does not prevent cytokinesisbut interferes with complete chromatide separation

histon-GFP Hoechst HeLa

securin

securinKAA-DM

securinKAA-DM

NIH3T3

Page 46: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

The three factors that enable sister chromatid separation

• The glue - cohesins

• The pulling force - the mitotic spindle

• The timing mechanism - spindle checkpoint

Page 47: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 48: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 49: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 50: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x
Page 51: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Anaphase Promoting Complex/Cyclosome

Page 52: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

APC

Checkpoint

cdk1Cyclin B

Fzy

CheckpointCheckpoint

Fzr

Polo

Prophase

Page 53: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

APC

cdk1Cyclin B

Fzy

CheckpointCheckpoint

Checkpoint

Fzr

Polo

Metaphase

Page 54: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

APC

cdk1Cyclin B

Fzr

FzyFzr

Fzy

Anaphase

Polo

cdc14

Metaphase

Page 55: A briefe history of the cell cycle 18xx Interphase-Mitosis 1951 Discovery of a distinct S-phase 1970 Cell fusion experiments 1971 Discovery of MPF 197x

Yes (chrom. movement)

MetaphaseMetaphaseChrom. alignment on metaphase plate

Xkid

?TelophaseMitosisE2 of the APC/C UbcH10

NoTelophase - G1MetaphaseAPC/C activatorFzy

Yes (cyclin A+B degr.)

PrometaphaseG2, prophaseKinaseNek2A

NoG1SReplicationCdc6

?Telophase - G1MitosisMitotic kinasePlk1

Yes (cytokinesis)

MetaphaseProphase- metaphase

Mitotic kinaseCyclin B1

Yes (chrom. separation)

MetaphaseS-metaphaseChromatid cohesion maintenance

Securin

Yes (metaphase)

PrometaphaseS, G2, prophase

Kinase (+cdk1/2)Cyclin A2

Degrad. essential

Degradation

initiated

ActiveRoleSubstrate


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