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Molecular Cell Bio > exam 3 > Flashcards

exam 3 Flashcards

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Biology 101 flashcards
1
Q

What is the cell cycle

A

A process in which cells reproduce by duplicating their contents + dividing it into 2: cell growth + chromosome duplication, chromosome segregation, cell division

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2
Q

3 main transition points of the cell cycle

A

G1>S: confirms env is favorable for proliferation before commiting to DNA replication

G2>M: confirms that the DNA is undamaged and fully replicated

M: ensures that the duplicated chromosomes are properly attached to the mitotic spindle

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2
Q

What is the cell-cycle control system

A

ensures that key processes occur in the proper sequence
control system is regulated at certain critical points of the cycle by feedback from the process currently being performed
has checkpoints to pause the cycle at certain points + does not trigger next step unless cell is prepared

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2
Q

What are the phases of the cell cycle

A

Interphase: cell grows continuously (otherwise it would shrink w/ each division)
> G1, S, G2
G1, G2 - gap phases, cell monitors internal state + external env
S - DNA replication

M: mitosis (nuclear division) + cytokinesis (cytoplasmic division)

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3
Q

Progression through the cell cycle depends on..

A

Cdks - cyclin-dependent protein kinases

must bind a cyclin (a regulatory protein) before it can become enzymatically active (where it then phosphorylates key proteins that are required to initiate particular steps in the cell cycle)

distinct Cdks associate w/ different cyclins to trigger diff events

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4
Q

changes in cyclin concentration

A

gradual increase in cyclin conc (due to transcription of cyclin genes + synthesis of cyclin protein)
rapid fall in cyclin conc (due to full-scale targeted destruction of protein)

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5
Q

cyclin-cdk complexes

A

G1-Cdk: cyclin D + Cdk4/6
G1/s-Cdk: cyclin E + Cdk2
S-Cdk: cyclin A + Cdk2
M-Cdk: cyclin B + Cdk1

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6
Q

Active cyclin-cdk complex > inactivation (cell-cycle control system)

A

active cyclin-cdk comples > ubiquitylation of cyclin by APC/C > destruction of cyclin in proteasome > inactive cdk + destructed cyclin

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7
Q

how to activate cdks (e.g M-cdk) (cell-cycle control system)

A

M-cdk complex forms + is immediately phosphorylated by an inhibitory protein kinase (Wee1)

this keeps m-cdk inactive until…

phasphates are removed by an activating protein phosphatase (Cdc25) = active M-Cdk

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8
Q

How can cdk activity be blocked (cell-cycle control system)

A

by the binding of a cdk inhibitor protein to an activated cyclin-Cdk complex

attachment prevents Cdk from phosphorylating target proteins + maintains complex in an inactive state

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9
Q

Which mechanisms are used to pause the cell cycle at which transition points

A

G1>S: Cdk inhibitors blocking entry to S phase (bc env is not favorable)

G2>M: inhibition of activation phasphatase (Cdc25) blocks entry to mitosis (bc DNA replication not complete + DNA damage)

Exit of mitosis: inhibition of APC/C activation delays exit from mitosis (bc chromosomes are not properly attached to spindle)

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10
Q

G1 phase overview: pathways + cdk inhibitors?

A

inhibitors: p15, p16, p18, p19
inhibit CDK4/6 + Cyclin D
cyclin D is produced/upregulated by: MAPK, PI3K, Wnt, NFkB
CDK4/6 + Cyclin D complex phosphorylates Rb = releases transcription regulator (E2F) = transcription of genes producing equired for S-phase entry (e.g cyclin A/E)

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11
Q

mitogens

A

extracellular signals produced by other cells that stimulate a cell to multiply

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12
Q

One way in which mitogens stimulate cell proliferation (G1)

A

inhibition of the Rb protein

absence of mitogens: dephosphorylated Rb hold specific transcription regulators in an inactive state

mitogens binding to cell-surface receptors activate intracellular signalling pathways that lead to the formation + activation of G1-Cdk and G1/S-Cdk complexes

Complexes phosphorylate = inactivate Rb protein = release transcription regulators = activate transcription of genes req for entry into S

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13
Q

DNA damage: Halt progression through G1

A

DNA damage > activation of protein kinases that phosphorylate p53 protein, stabilizing + activating it > activated p53 accumulated + stimulates transcription of the gene that encodes the Cdk inhibitor protein (p21) > p21 protein binds to G1/S-Cdk and S-Cdk and inactivates them = cell cycle arrests in G1

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14
Q

permanent vs temporary withdrawl from cell cycle

A

permanent: terminally differentiated cells = cell-cycle control system is dismantled completely + genes encoding relevant cyclins + Cdks are irreversibly shut down

temporary: absence of appropriate signals = enter an arrested state called G0. They retain the ability to reassemble the cell-cycle control system quickly + divide again

15
Q

S phase overview: inhibitors + proteins

A

inhibitors: p21, p27, p57

16
Q

Initiation of DNA replication: S phase steps

A

During G1, Cdc6 binds to the ORC (origin recognition complex), together these load a pair of DNA helicases on the DNA + the Cdc6 dissociates = forms the prereplicative complex.

At the start of S phase, S-Cdk triggers the firing of this loaded replication origin by guiding the assembly of the DNA polymerase + other proteins that initiate DNA synthesis at the replication fork.

17
Q

how can S-Cdk block re-replication

A

by phosphorylating Cdc6 and the ORC = keeps these proteins inactive + prevents the reassembly of the prereplicative complex until the Cdks are turned off in the next G1

18
Q

What happens if there is incomplete replication

A

Activity of M-Cdk is inhibited
DNA damage response is triggered:
Inhibition of phosphatase Cdc25 = prevents removal of the inhibitory phosphates from M-Cdk = M-Cdk remains inactive

19
Q

Role of M-Cdk

A

helps prepare the duplicated chromosomes for segregation + induces the assembly of the mitotic spindle

20
Q

How is M-Cdk activated

A

Activating phosphatase Cdc25 removes the inhibitory phosphates holding M-Cdk in an inactive state
self-reinforcing process: M-Cdk phosphorylates + activates more Cdc25 (positive feedback increasing M-Cdk activity which drives G2 into M phase)

21
Q

Stages of mitosis

A

prophase, prometaphase, metaphase, anaphase A, anaphase B, telophase

22
Q

Going from metaphase to anaphase

A

APC/C triggers the separation of sister chromatids by promoting the destruction of cohesins.

APC/C indirectly triggers the cleavage of the cohesins that hold sister chromatics together. It catalyzes the ubiquitylation and destruction of an inhibitory protein called securin, which blocks the activation of separase (a protease). When freed from securin, separase cleaves the cohesion complexes, allowing the mitotic spindle to pull the sister chromatids apart

23
Q

Two processes segregate chromosomes at anaphase

A

Anaphase A: (kinetochore microtubules shorten + chromosomes move poleward) sister chromatids are pulled toward opposite poles as the kinetochore microtubules depolymerize

Anaphase B:
spindle poles move apart as a result of 2 separate forces:
1) elongation + sliding of the interpolar microtubules past one another pushes the 2 poles apart
2) forces exerted on the outward-pointing astral microtubules at each spinfle pole pull the poles away from each other, toward the cell cortex

24
Q

Nuclear envelope break down + re-forming

A

Phosphorylation of nuclear pore proteins + lamins help trigger the disassembly of the nuclear envelope at prometaphase. Dephosphorylation of nuclear pore proteins + lamins at telophase help reverse the process (continued fusion of nuclear envelope vesicles)

25
Q

What is Metaphase checkpoint

A

Prevents premature segregation of sister chromatids by delaying anaphase onset until all chromosomes are correctly attached to the spindle apparatus

If any chromosome is improperly attached, SAC proteins inhibit APC/C activation.

Once all kinetochores are properly attached, SAC inhibition is lifted, APC/C degrades Cyclin B1 and Securin, and anaphase proceeds.

26
Q

When does the mitotic checkpoint activate

A

during prometaphase

27
Q

the process of achieving stable microtubule attachments at the kinetochores

A

Unstable Attachments:
Microtubules initially bind kinetochores in incorrect or unstable orientations.
These unstable attachments are corrected through trial-and-error (via tension sensing)

Stable Attachment:
When microtubules attach properly (with tension generated between sister kinetochores), the attachments are stabilized.
Stable attachments satisfy the SAC, allowing progression to anaphase.

28
Q

Cells + DNA content levels

A

G1: 2N (normal diploid amount of DNA, has not replicated its DNA yet)

S: DNA replication occurs = DNA content gradually increases to 4N

G2: 4N (replication is fully complete)

29
Q

Summary of cell cycle

A

Initiation of cell cycle progression by RAS/NOTCH/WNT pathways
G1 phase: Restriction point and preparation for DNA replication
S phase: DNA replication
G2 phase: DNA damage checkpoint and preperation for mitosis
M phase: Mitotic checkpoint and mitosis
Cell cycle analysis using Flow cytometry

30
Q

Neuroblastoma

A

blued eyes, pain, swollen stomach
origin: adrenal glands
treatment: surgery, chemotherapy, radiotherapy, maintenance of remission treatments

31
Q

What is cancer

A

aberrations in DNA (genomic or epigenomic)

32
Q

How can genomic aberrations in DNA lead to cancer

A

DNA aberrations (genotype) > Aberrant mRNA expression > Aberrant protein expression > Aberrant cellular processes (phenotype)

Too much: gain, amplification
Too little: loss of heterozygosity, deletions
Structural / sequence changes: translocations, mutations

how to identify which type of genomic aberration?
Via next generation sequencing: sequence order, copy number, translocations

33
Q

Which types of generations are there in sequencing (to determine genomic aberrations?)

A

1st: conventional sequencing
2nd: massive parallel sequencing
1) Build a library of small DNA fragments with known linkers
2) Amplify and attach fragments to patterned surface (every fragment is separated from rest)
3) Determine sequence of large amount of
fragments. Readout of bases via image overlay (e.g circos plots)

34
Q

Cell Cycle Aberrations in Neuroblastoma

A

Gain/amplification > overexpression of cell cycle proteins (e.g., Cyclin D) or (e.g., CDK4, CDK6) = unchecked cell proliferation
LOH/deletions in tumor supressor genes e.g RB = loss of cell cycle control
Changed > RB pathway is disrupted: Hyperactive Cyclin D-CDK4/6 complexes phosphorylate RB, rendering it inactive and unable to suppress the G1/S transition. Loss of CDK inhibitors like p16, p21, p27, and p57 further accelerates this process.

35
Q

What is overexpressed in neuroblastoma

A

Cyclin D1

36
Q

Conclusions on cell cycle targets in neuroblastoma

A

DNA: Genomic aberrations G1 checkpoint
mRNA: Strong overexpression of Cyclin D1
siRNA/CRISPR: experimental targetting where Cyclin D1 is knocked out/edited = cytostatic effect (altering cell division without necessarily inducing cell death - preventing proliferation of NB cells) + CCND1 crucial gene in NB
Actionable target genes are kinases for therapeutic effects

37
Q
A

Molecular Cell Bio (3 decks)

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