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MD2002 > Cell Division > Flashcards

Cell Division Flashcards

1
Q

Identify the stages of cell division, and the fcuntion of each.

A

INTERPHASE-
G1 phase (longest phase): checking if enough nutrients, etc.
to move into cell division
S phase: DNA replication
G2 phase: check that all genetic info accurately replicated and ready to move into mitosis

MITOSIS-
Mitosis (shortest phase): Consists of division of nucleus + division of cytoplasm

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2
Q

What is the main class of enzymes controlling the cell cycle ?

A

Cyclin dependent kinases

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3
Q

How are CDKs activated/inactivated ?

A

Initially inactive: active site of CDK sterically inhibited by T loop
Activated by binding of cyclins (co-factor. Upon cyclin binding to CDK, T loop pulled away from active site and expose bound ATP, allowing access to target proteins) + phosphorylation (CDK activating kinase adds phosphate to threonine in the T loop and inhibitory kinase adds inhibitory phosphate to threonine/tyrosine) and dephosphorylation (acivating protein phosphatase removed inhibitory phosphate).

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4
Q

Describe the concentration of cyclin and activity of CDKs in the different cell division stages.

A

INTERPHASE:

  • cyclin concentrations at lowest during G1, progressively increases through S and G2.
  • CDK activity mainly non-existant (because not until cyclin concentrations rise to certain levels that Cdk become active)

MITOSIS:

  • cyclin concentrations reach maximum
  • CDK activity high
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5
Q

Describe how phosphorylation and dephosphorylation regulate CDK activity.

A
  1. Cyclin-cdk complex initatlly inactive
  2. Then phosphorylated on two sites (one is inhibitory, one is activating) by protein kinases
  3. Cell makes sure all conditions are satisfied for mitosis to take place
  4. An activating Phosphatase comes and removes inhibitory phosphate, resulting in active complex
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6
Q

Describe the normal role of CDC25 and wee1 proteins, and hence the result of CDC25 and wee1 mutations.

A

CDC25: Activating phosphatase which removes inhibitory phosphate (hence, promotes activation of CDKs)

Wee1: Inhibitory kinase which puts inhibitory phosphate on Cdk (inducing interphase and preventing entry into mitosis, hence preventing cell from dividing when very very small)

CDC25 mutant: lacks CDC25 so no signal to move into mitosis so arrive at size for division (since main overriding factor determining cell division in yeast is size) but continue growing. Results in division at bigger size than normal.

Wee1 mutant: lacks wee1 so nothing preventing early entry into mitosis. Results in cell able to divide at very small size.

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7
Q

What is the main overriding factor determining when cell division begins, in fission yeast ?

A

Size of the cell

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8
Q

What mutations are responsible for division of abnormally big and abnormally small cells in fission yeast ?

A

CDC25 mutations: division of abnormally big cells

Wee1 mutations: division of abnormally small cells

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9
Q

Which specific proteins are responsible for the following in fission yeast:

  1. Putting inhibitory phosphate on CDK
  2. Putting activating phosphate on CDK
  3. Removing inhibitory phosphate on CDK
A
  1. Putting inhibitory phosphate on CDK: Wee1 (inhibitory kinase)
  2. Putting activating phosphate on CDK: CaK (CDK activating kinase)
  3. Removing inhibitory phosphate on CDK: CDC25 (activating phosphatase)
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10
Q

Describe the concentrations of M cyclins and S cyclins during the different stages of cell division, and identify when exactly S-CDK and M-CDK become activated as a result.

A

The concentrations of S cyclins begins to rise halfway through G1, reaching a maximum at G1/S boundary (which is when S-CDK becomes activated). The concentrations of S cyclins then remains constant at said maximum until the beginning of M phase at which point it progressively decreases (reaches 0 halfway through mitosis)

The concentration of M cyclins is null during G1 and S phases. It begins rising during G2 and reaches a maximum at the G2/M boundary (which is when M-CDK becomes activated). Soon after, still during mitosis, the concentration of M cyclins begins to decreases (reaches 0 halfway through mitosis, a little after S cyclins after reached 0)

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11
Q

Identify the specific components (specific cyclin and specific enzyme) of the main cyclin-CDK complexes, and state the stages of cell division which each complex controls.

A

D cyclin and CDK4/6 (most of G1, until R point)
E cyclin and CDK2 (G1 after R point and some of S)
A cyclin and CDK2 (half of S)
A cyclin and CDC2 (=CDK1) (other half of S and G2)
B cyclin and CDC2 (=CDK1) (M phase)

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12
Q

How are Cyclin-CDK complexes inactivated after fulfilling their role ?

A

Cyclin part is ubiquitilated
This tells the cell machinery to destroy the cyclin
CDK becomes inactive

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13
Q

At which stage of cell division is Cyclin B destroyed ?

A

At the end of mitosis

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14
Q

Describe the process of ubiquitination of cyclins.

A
  1. Ubiquitin covalently bound to E1 activating enzyme (there are 2 E1 enzymes in mammalian cells). Energy consuming process generating high energy bond.
  2. Ubiquitin eventually transferred to E2 conjugating enzyme (35 E2 enzymes in cells).
  3. Once transferred, it can work in junction with E3 ubiquitin ligase to specifically ubiquinate its favourite substrate (E3 enzyme provides substrate specificity). (100s of these, specific for different substrates in human cells)

Ubiquitin usually transferred to lysine on substrate to generate this kind of bond. Ubiquitins themselves may be polymerised to generate a chain.

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15
Q

Where does destruction of cyclins take place ?

A

Proteasome

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16
Q

Describe how the structure of proteasomes helps in its function of cyclin destruction.

A

Core particle in middle forming channel
Regulatory part in top and bottom
Particular proteins in the regulatory particle which recognise ubiquitin
They start to cleave off ubiquitin (which can be re-used) and unfold protein (so can move in energy dependant manner through core aprticle)
In core particle, protein is chopped up into constituents AAs, which are lost out of the bottom of proteosome

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17
Q

How many Sverdberg units does a proteasome have ?

A

26S

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18
Q

What are possible ‘errors’ which cellular checkpoints must check for ?

A
  • Damaged DNA
  • Incompletely replicated DNA
  • Unfavorable extracellular environment
  • Chromosome improperly attached to mitotic spindle
19
Q

What is the general function of (active) kinase enzymes ?

A

Transfer phosphate groups from ATP to serine and threonine side chains on target protein

20
Q

How do CDK inhibitors work structurally ?

A

Some inhibitors bind directly at kinase active site and block kinase activity by interfering with ATP binding.
Others bind near active site and interfere with substrate binding.

21
Q

Describe what happens in the R-point.

A

R-point = G1/S transition
-Essentially, chooses either growth (move into synthesis) or quiescence

1) In non-proliferating cell:
-CDK is kept in inactive form because CDK inhibitor present
-Hence specific protein (Rb) is unphosphorylated, so active and bound to transcription factor adjacent to certain genes.
-Tells cell not to transcribe genes, we do not want to move
into S phase, so do not want S phase specific genes expressed, like for DNA polymerase

2) In proliferating cell (ready to divide)
- Cyclin dependant kinase inhibitor inactivated or not present at all
- CDK activated, and ready to phosphorylate its first substrate (target protein)
- Key target protein in G1 to S phase transition is Rb protein
- Rb becomes phosphorylated, inactive, and falls off DNA
- Transcription factors become active, so get synthesis of genes required for entry into S phase

22
Q

What is the most important regulatory stage of cell cycle ?

A

R point

23
Q

Clinically, why are defects in genes required to pass the R point important ?

A

Because they underlie many tumours (mutations in Rb protein, in cyclins (possibly upregulated), in CDKs (possibly upregulated)

24
Q

What is a possible treatment option for cancer, targeting the R point ?

A

Specific inhibitors of CDK4/6

25
Q

What are the main protein targets of CDKs ?

A
  1. Rb during the R point

2. CDC6 past the R point (to trigger S phase)

26
Q

Explain how and why CDK targets CDC6.

A

-CDC6 involved in control of replication from DNA site called origin of replication
-Origin of replication normally bound by complex including CDC6
-DNA polymerase cannot bind to this complex so unable
to start DNA replication
-When cell moves into S phase, S-CDK phosphorylates CDC6, which then falls off pre-replicative complex
-This means proper replication fork can assemble at origin of replication and DNA synthesis at that specific origin can start (hence, S-CDK triggers S phase)

27
Q

How do cells ensure that phosphorylated CDC6 cannot somehow rebind to replicative complex ?

A

CDC6 is degraded by ubiquitin specific pathway

28
Q

Describe the main mechanisms by which transcription of cell cycle can stop (following DNA damage).

A

2 main ones:

  • p53: directs transcription of cdk-inhibitors (directs transcription of cdk-inhibitors, which structurally interfere with active CDK and convert it into inactive form)
  • CHK2 (inhibits cdc25 which is phosphatase responsible for final step of activating CDK)
29
Q

Describe the stages of mitosis.

A

PROPHASE
Nuclear envelope intact
Chromosomes are intact within nucleus
Microtubules beginning to be organised

PROMETAPHASE
Chromosomes begin to condense
Nuclear envelope breaks down

METAPHASE
Chromosomes become aligned on central spindle
Chromosomes attached to spindle such that tension between the chromatids and each chromatid attached to microtubules from opposite ends of spindle (do not line up with both chromatids on same side of spindle)
Specific checkpoint checking that chromosomes are attached properly

ANAPHASE
Separation of chromosomes to opposite ends of spindle which finishes in TELOPHASE

CYTOKINESIS
Division of cytoplasmic components and separation of the cells

30
Q

How does DNA condensation occur ?

A

Condensins form handcuffs around DNA and help it become more compact

31
Q

When does DNA reach its maximum condensation ?

A

Metaphase

32
Q

How does the mitotic spindle form ?

A
  • Centrosome comprises 2 centrioles
  • These are replicated early in cell cycle (S/G2) and start to organise microtubules (which make up astral rays) even before mitosis is fully underway (done in time for metaphase)
33
Q

What does nuclear envelope breakdown and reformation take place ?

A
  • CDK target nuclear lamines (proteins found on inside of nuclear envelope) and pore proteins
  • When proteins become phosphorylated by CDK, that contributes to falling apart of nuclear envelope in prometaphase
  • Dephosphorylation of Nuclear Pore proteins and nuclear lamines contributes to the later formation of the nuclear envelope in telophase by allowing fusion of nuclear envelope vesicles (which were bound to phosphorylated lamins)
34
Q

How do chromosomes attach to spindle ?

A

-Through constricted region present in centromere of chromosomes (kinetochore)
-These kinetochores bind directly to microtubules
-Need to bind to microtubules at both ends of the
spindle

35
Q

Why do some chemotherapy drugs target metaphase ?

A

Because by rendering the spindle abhorrent, it results in the end of division and death of the cell

36
Q

How are sister chromatids held together ?

A

Through cohesin rings (hold them together until the right stage of the cell cycle)

37
Q

Describe Roberts Syndrome.

A

Due to defect in cohesion of sister chromatids (further apart)
Mutation on 8th chromosome
Very rare
Limb and facial abnormalities

38
Q

How are sister chromatids separated in anaphase ? How is this regulated ?

A

Separase (proteolytic enzyme) chopps up cohesins into AAs such that chromosomes under tension attached to opposite ends of spindle can now move apart (results in cleaved and dissociatied cohesins)

  • Separase normally kept in inactive form (dimer with inhibitory protein called securin).
  • At right stage of cell cycle, Anaphase Promoting Complex is E3 ubiquitin ligase and targets securin for ubiquitylation and subsequent degradation
  • Without inhibitor protein (securin), separase becomes active and can chop up cohesins to release chromosomes
39
Q

What are possible consequences of defects in separation of sister chromatids ?

A

Paired chromosome moving to same end

40
Q

What happens if cyclins and securins are not degraded by ubiquitination pathway ?

A

Cells unable to exit mitosis

41
Q

What are possible consequences of defects at spindle checkpoint (between metaphase and anaphase) ?

A

Aneuploidy (“presence of an abnormal number of chromosomes in a cell”), which “is consistently observed in virtually all cancers”

42
Q

How does cytokinesis take place ?

A
  • Separate cytoplasm into the two daughters
  • Done through contractile ring of actin and myosin in cleavage furrow at central point where center of spindle was (interpolar microtubules from central spindle still present on either side of contractile ring in the cell)
43
Q

What are the main control points within the cell cycle ?

check answer is accurate here, normally should be good

A

1) Control of CDK-Cyclin levels through:
- p53: Cyclin dependent kinase inhibitors (regulate CDK-cyclin complex levels)
- CHK2: inhibits cdc25 which is phosphatase responsible for final step of activating CDK (hence keeps CDK inactive)

Overall, CDK-cyclin complex levels important for R point (Rb), in G1/S boundary (Cdc6), to break down nuclear envelope (lamine)

2) Degradation of cyclins and securin (important for mitotic exit)

MD2002 (108 decks)

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