Cell Cycle

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  • Created by: Ezz96
  • Created on: 15-01-17 13:57
Centrosomes
Organise the spindle where spindle divides and where microtubules organise
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G1
10 hours. Metabolic changes prepare cell for division
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S phase
6 hours. DNA synthesis - 2 sister chromatids for each chromosome
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G2
3-4 Hours. Metabolic changes assemble the cytoplasmic materials for mitosis
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M
8 Hours. Mitosis - nuclear division then cell division (cytokinesis)
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Cyclin D 1,2,3
Cdk4 and Cdk6 (involved in G1)
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Cyclin E
cdk2 (involved in G1/S )
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Cyclin A
Cdk1 (mitosis) and cdk2
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Cyclin B (major mitotic cyclin, replaces cyclin A on cdk1 as cells reach mitosis)
cdk1 (mitosis)
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Inhibitors of cdk activity
Wee1 and Myt1
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Wee1 (G2 Checkpoint)
Phosphorylates Tyr15. It is a tyrosine kinase of Ser/thr family. Nuclear
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Myt1 (G2 Checkpoint)
Phosporylation Try15 and Thr14. Membrane-associated and cytoplasmic.
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Cdc25 (A, B, C in humans)
Counteracts Wee1 and Myt1. It is a phosphatase and dephosphorylates cdk to activate it.
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Full Cdk activity requires phosphorylation by cdk-activating kinase (cdk7 in humans)
1. cdk's are inactive alone. They bind to cyclin partner to form active heterodimer.
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Cks1 protein (cksHs1 and cksHs2)
Adapter to target cdk's to phosphoproteins. They also mediate APC interaction with cyclin A and B (mediating their destruction). Additionally enhances multiple phosphorylation of some M-cdk substrates by increasing affinity to substrate.
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Cdk Inhibitor proteins
Suppressors of cdk activity in G1. Responsible for maintaining G1 arrest during adverse conditions or with DNA damage. Loss of function is linked to cancers.
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SCF
E3 Ubiuitin ligase - controls G1/S transition to remove cyciln components. Core subunits: RBX1 (ring finger) Cullin (Cul1) SKp1. Also has an E2 ubiquitin target protein.
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3 major checkpoints of the cell cycle
1. DNA damage checkpoint G1/2 2. DNA replication checkpoint G2/M 3.Spindle Assemby Checkpoint - during mitotis before anaphase
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If DNA damage is detected
P53 will be phosphorylated and activated and causes the production of cdk inhibitor protein - cell cycle arrest. P21 levels increase - inhibitor of early kinase activity
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DNA synthesis direction
5'-3'
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RPA (replication protein)
Site of binding for primers
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Sliding clamp (PCNA)
forms closed ring around the DNA to hold polymerase on DNA strand
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DNA helicase
MCM2-7 unwinds DNA
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Geminin
inhibits cdt1, accumulates during S and G2 phase and is degraded by APC, it prevents a second round of synthesis
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Chromatin core structure
4 Core histones, duplicated to form an octomer: H2A, H2B, H3, H4
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CAF-1
Assembly factor that complexes with H3-H4 tetramer
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NAD-1
Assembly factor(2) that forms the octomer by joining H3-H4 with H2A-H2B
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Cell Cycle Kinases
Polo-like-kinases (PLK), Aurora A, and Aurora B
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Polo-Like-Kinases (PLK)
PLK1 - Regulates spindle assembly and mitotic exit (activated in early mitosis) PLK4 - Regulates centrosome separation and cleave furrow formation
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Aurora A and Aurora B
Both regulate spindle function and chromatid separation. Aurora A functions at centrosomes to maintain spindle integrity. Aurora B forms part of the chromosomal passenger complex (CPC) Aurora B also helps cyclin A package chromosomes
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Chromosomal Passenger Complex (CPC)
Aurora B, INCENP, survivin, borealin. On chromosome arms during early mitosis then moves to centromeres and kinetechores to: aid in chromosome condensation and to promote correct microtubule to kinetechore attachment
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PP1
Opposes Aurora B, present until prophase then anaphase B to telophase. Inhibited by I-2
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Difference between mitosis and meiosis
Synaptonemal complex only in meiosis (crossing over) 2 rounds of division in meiosis. Centromeric cohesion protected in meiosis 1 only, also cyclin B destruction whilst SAC is on. Polar body in meiosis. Different cohesion complexes.
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Separase digestion in meiosis
1. Separase cleaves arms in meiosis 1 in metaphase1 - anapase1 transition. 2.Separase cleaves protected cohesion (around centromeres) so chromatids can separate during meiosis 2 in the metaphase2-anaphase2 transition
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REC 8
Protected cohesion, keeps sister chromatids together during meiosis 1
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Emi1
Blocks APC activity, mediating second transition in meiosis. Stops cyclin destruction in metaphase 2 so egg is arrested waiting for fertilisation. Broken to let zygote develop.
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Trisomy 18
Edward Syndrome
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Trisomy 13
Patau syndrome
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Trisomy 21
Down syndrome
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Problem with anti-mitotic drugs
1. Neuronal cell are susceptible (depend on microtubule integrity) and can be damaged causing neuropathy. 2. Difficult to target specific window as kinases can have multiple roles 3.Drugs may have cytotoxicity if they inhibit more than just target
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Slippage
Cells escape mitotic arrest (destruction of cyclin B even with SAC inhibiting APC)
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Effect of cyclin B1 levels falling quickly
Slippage prone cell lines
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Affect of death signals accumulating quickly
Death prone cell lines
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Fall of cyclin B1 and rise of death signals finely balanced effect
Heterogenous fate profile
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Card 4

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Card 5

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