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MIMS- cell cycle and cancer > cell division > Flashcards

cell division Flashcards

1
Q

configuration of chromosomes for segregation

A

cohesins and condensins work together to configure the replicated chromosome in preparation for mitosis

  • cohesins: when the chromosomes are duplicated in S phase they remain tightly bound as sister chromatids by protein complexes called cohesins
  • condensins: chromosome compaction/condensation
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2
Q

which cytoskeletal machines are assembled (in sequence) to perform the mechanical processes of mitosis and cytokinesis?

A
  • a bipolar mitotic spindle performs mitosis

- a contractile ring performs cytokinesis

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3
Q

what is the mitotic spindle composed of?

A

it is composed of microtubules and various proteins including microtubule-dependant motor proteins

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4
Q

what is the contractile ring composed of? where does it form?

A

it contains both actin and myosin filaments.

it forms around the equator of the cell under the plasma membrane

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5
Q

what is bi-orientation?

A

it’s achieved when sister chromatids attach to microtubules that emanate from opposite ends of the mitotic spindle

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6
Q

when is cohesin cleaved?

A

at the start of anaphase; once all the chromosomes have attached to microtubules

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7
Q

what is kinetochore? what is its function?

A

the kinetochore is a hierarchical protein assembly of nearly 100 proteins that links centromeric DNA to spindle microtubules and thereby couples force generated by microtubule dynamics to power chromosome movement

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8
Q

what is also known as the Mitosis-promoting factor? why?

A

cyclinB-CDK1 complex (M-CDK).

because, increase in CycB-CDK1 triggers entry into mitosis

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9
Q

what are the structural components of the kinetochore?

A

the two parts of Kinetochore:

  1. CCAN = constitutive centromere associated network
  2. KMN-network= ‘KMN’ stand for KNL1, Mis12, and Ndc80 complexes
  • CCAN forms the centromeric chromatin (the chromatin of the kinetochore that is in association with the CENP-A-containing nucleosomes present in the centromere)
  • the Ndc80 in the KMN network makes a direct contact with the microtubules of the spindle
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10
Q

what is Aurora B? where does it localize during different stages of the cell cycle?

A

Aurora B is a kinase.
it localises to–> chromosomes in prophase; centromeres in prometaphase and anaphase; central mitotic spindle in anaphase

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11
Q

how do the phosphorylation levels of aurora B substrates change with mitotic progression?

A

until the establishment of the bipolar attachment (pro-metaphase) –> aurora B substrates on the kinetochore are highly phosphorylated

once the bipolar attachment is established (metaphase), the kinetochore is stretched by the force from microtubules–> the substrates that are away from the centre of aurora B activity (in the inner-centromere) start to be dephosphorylated by PP1 (protein phosphatase 1) which is located in the outer-kinetochore

during anaphase–> aurora B activity moves to the central mitotic spindle and its substrates are further dephosphorylated

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12
Q

what is the greatwall pathway? what is its significance in terms of mitotic exit?

A

-The greatwall pathway ensures that separase activation and chromosome segregation is followed by cytokinesis

  • In this pathway:
    (i) separase inhibition is maintained by CycB concentration, and,

(ii) PP2A-B55 inhibition is coupled to CycB-Cdk1 (M-Cdk) activity; [so, when the M-Cdk is active, even PP2A-B55 is inhibited, and vice versa]

this creates two CycB thresholds during mitotic exit so that the first threshold permits separase activation and chromosome segregation and the second threshold permits PP2A-B55 activation and initiation of cytokinesis–> therefore, the significance of the pathway is that it promotes temporal order during mitotic exit

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13
Q

what are the structural and functional changes in centrosomes as it transitions through the cell cycle? how are these changes controlled?

A

the changes include:
(i)change in number of centrosomes

(ii)modulation of centrosome activity i.e. the number of microtubules nucleated and anchored at the centrosome

these changes are by centrosome duplication and centrosome maturation cycles respectively

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14
Q

what is the centrosome composed of? what is its (and its components) structure?

A

each centrosome has 2 centrioles– maternal and daughter
each centriole has a nine-fold symmetry (i.e., 9 triplets of microtubules) and a proximal-distal polarity

each centriole is surrounded by pericentriolar material (a protein rich material) present between the ends of the two centriole closest to each other
A series of interconnecting fibres (different to the PCM), links the closest ends of the two centrioles

ONLY the maternal centriole has 2 extra sets of appendages; these are–> distal and subdistal appendages
*the subdistal appendages seems to anchor microtubules (astral MTs?) to the maternal centriole

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15
Q

What is the function of the centrosome

A

In mitosis, two centrosomes organise the pole of the mitotic spindle and mediate microtubule positioning through the interactions of their astral microtubules with the cell cortex

In interphase, centrosomes and their anchored MTs regulate the positioning of many molecules and structures such as nuclei and the golgi along with the stability of cellular junctions and adhesions, helping to define cell shape and polarity

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16
Q

what is the function of a centriole? what are its special features?

A

It organises centrosomes and cilia and is important for cell signalling, cell cycle progression, polarity, and motility

It is an evolutionarily conserved structure that is built from highly conserves proteins

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17
Q

diseases related to defects in centrioles

A

cancers and ciliopathies

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18
Q

what is the diameter and length of a typical centriole in a human somatic cell?

A

about 200-220nm diameter

500nm length

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19
Q

what triggers the progression from metaphase to anaphase? What is it?

A

activity of APC (anaphase-promoting complex)

It is an E3 ubiquitin protein ligase

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20
Q

what are the main targets of APC?

what is the effect of the degradation of its targets respectively?

A

Securin and cyclins

destruction of securin leads to separation of sister chromatids
destruction of cyclins results in a drop in Cdk activity;

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21
Q

What is the result of a drop in Cdk activity in the transition from metaphase to anaphase (i.e.during late mitosis)?

A

Cdk inactivation allows cellular phosphatases to dephosphorylate Cdk substrates
Cdk substrate dephosphorylation is required for the events of anaphase and telophase

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22
Q

Which cyclins are present in high concentrations in the cell during entry into mitosis?
These cyclins are sequentially destroyed as mitosis progresses. what is the sequence?

A

Cyclins A, B, and B3

cyclin A is degraded soon after nuclear envelope breakdown
cyclin B is degraded immediately after the last sister-chromatid pair is bi-oriented on the spindle (at the beginning of metaphase)
cyclin B3 is destroyed after cyclin B (around the beginning of anaphase)

23
Q

When in the cell cycle does securin degradation occur? it occurs at the same time as the degradation of which specific cyclin?

A

It occurs immediately after the last sister chromatid pair is bi-oriented, at the beginning of metaphase
It is degraded at the same time as cyclin B

24
Q

Stabilized forms of each cyclin (A, B, B3) were constructed (by mutating the sequence required for recognition by the APC)
Expression of the cyclins during G2 resulted in mitotic arrests which were at a different phase for the different stabilized cyclins.

Which phases did each specific cyclin cause a mitotic arrest?

A

stable cyclin A caused an arrest in metaphase
stable cyclin B caused an arrest in anaphase
stable cyclin B3 caused an arrest in late anaphase

NOTE: these arrests are at a phase that is a bit after the degradation of each cyclin starts normally; this is because it takes a while to substantially decrease the concentration of that cyclin in the cell and so usually the effect of the cyclin depletion is shown a little while after its degradation starts;

25
Q

What are the key kinases involved in cell division?

A

CDK1
Aurora B
PLK1

26
Q

How does activity of CDK1 change during metaphase, anaphase and telophase respectively?

A

CDK1:
high activity in metaphase
low activity in anaphase
Inactive in telophase

27
Q

What is the localization of Aurora B during different stages of the cell cycle?

A 
Aurora B is located (and active) in:
chromosome (in general) in prophase 
centromere in prometaphase and metaphase 
central mitotic spindle in anaphase 
midbody in early telophase

and, in late telophase it is inactive and present in midbody derivative

note:
midbody is a transient structure present at the end of cytokinesis (just prior to complete separation of the cells); it contains microtubules and proteins involved in cytokinesis
midbody derivative is the remnant of midbody which is present in daughter cell after cytokinesis

28
Q

Which phosphatases play an important role in mitosis? state the role.

A 
phosphoprotein phosphatases(PPPs):
PP1

PP2A-B56 & PP6

PP2A-B55

Other phosphatases:
Cdc25- dephosphorylates and activates cycB/Cdk1 complex

Fcp1
etc.

29
Q

What is the function of PP1 in mitosis?

A

Substrates of PP1 are on the centrosome-kinetochore association
PP1 regulates the splitting of centrosomes;
PP1 functions by dephosphorylating the Aurora B substrates (including Ndc80, KNL1 and CENP-E) and then stabilizes the kinetochore-microtubule interaction and silences the spindle checkpoint

30
Q

What is the function of PP2A-B56?

A

It dephosphorylates the substrates of M-Cdk;

its substrates form the kinetochore-microtubule association

31
Q

Three different APC complexes predominate during different stages of mitosis and order the destruction of three different groups of proteins.

What are the 3 different complexes? how do they form successively? what are their targets?

A
  1. APC-Cdc20-SAC
    during early prometaphase the APC is first activated by its activator Cdc20 which is initially inhibited by components of the SAC (spindle assembly checkpoint)

This partially activated complex targets CycA and other proteins

  1. APC-Cdc20
    as bi-orientation takes place (in metaphase) and the SAC is inactivated, fully activated APC-Cdc20 now targets additional group of proteins–>CycB and securin
  2. APC-Cdh1
    As CycB is broken down and M-Cdk is inactivated (by the end of metaphase), its substrate, Cdh1 is dephosphorylated and activated.

Cdh1 is the second APC activator and the APC-cdh1 complex has a broader substrate specificity than APC-cdc20 and triggers destruction of various additional targets including Cdc20, Plk1, Aurora kinases (A and B) (in this order)

32
Q

What are the features of cytokinesis?

A

during cytokinesis the cell membrane pinches in at the cell equator, forming a cleavage furrow
the cleavage furrow forms because of the actions of a contractile ring of overlapping actin and myosin filaments
the position of the cleavage furrow depends on the position of the astral and interpolar microtubules during anaphase (the orientation of the cleavage furrow and contractile ring is perpendicular to the polar axis of the spindle)
a precise orientational relationship between the cleavage furrow and the mitotic spindle ensures that the chromatids separated during anaphase will be evenly distributed, guaranteeing identical copies of genetic material between the daughter cells

33
Q

summary of molecular events during cytokinesis

A

(a) This signalling between the anaphase (mitotic) spindle and the cortex generates an equatorial zone of active RhoA (RhoA is a G protein)
Meanwhile, the central spindle, which is a narrow zone of bundled overlapping microtubules, forms in the midzone between the separating chromosomes

(b) active RhoA directs assembly of the contractile ring

(c) contractile ring is a filamentous network composed of actin and myosin filaments
(d) as the contractile ring constricts the midzone matures to form midbody, which organises the intracellular bridge

(e) during abscission a distinct ESCRT-III filament system catalyses membrane scission on either side of the midbody to generate two daughter cells

34
Q

What happens when chromatin is trapped in the cleavage plane during cytokinesis?

A

Aurora B kinase is present at the midbody arms and is usually in an inactive state at the end of telophase, but, the stuck “lagging chromatin” results in activation of the Aurora B
the aurora b then phosphorylates CHMP4C to cause its localization to the flemming body where it delays abscission—> this is the No-Cut checkpoint
aurora b also activates condensin to compact chromosomes in order to clear the cleavage plane

NOTE: chromosome bridges frequently result in the abortion of cytokinesis and the formation of tetraploid cells that may promote tumorigenesis

35
Q

What is the flemming body in cytokinesis?

A

it is the central region of midbody; it is a dense structure of antiparallel microtubules from the central spindle in the middle of the intercellular bridge

36
Q

Importance of cytokinesis

A

each daughter cell must receive other cell components such as mitochondria, ER and lysosomes from the mother cell as they cannot be made de novo from individual components and so must be formed from pre-existing organelles by growth and fission. the number of organelles therefore also approximately double each cell cycle

37
Q

Which checkpoint causes arrest at what point of the cell cycle if DNA replication is perturbed or there are lesions in DNA?

A

DNA replication checkpoint/G2/M checkpoint

38
Q

which checkpoint arrests cell cycle until all the chromosomes are aligned on the spindle?

A

the SAC (spindle assembly checkpoint) arrests the cell cycle at M phase until all chromosomes are aligned on the spindle

39
Q

Why is SAC important?

A

it is important for equal distribution of chromosomes, i.e., it prevents defects in chromosome segregation

a defective SAC may provoke unequal inheritance of the genetic information that, if unrepaired, may facilitate tumour progression by accumulating numerical chromosomal aberrations

40
Q

What does the satisfaction of the SAC checkpoint trigger, i.e., what is SAC activity actually?

A

satisfaction of SAC triggers mitotic exit by promoting degradation of M-CDK (Cdk1)
SAC is a signalling pathway that modulates CDK1 activity;

41
Q

What does the SAC actually monitor? what is it also called?
[hint: it’s name is misleading]
When is the SAC ‘on’ and when is it ‘off’?

A

SAC monitors the kinetochore-microtubule attachment;
It is also called the mitotic checkpoint
the SAC is ‘on’ when the kinetochores are unattached – the anaphase is thus inhibited at this stage

the SAC becomes satisfied when all the kinetochores are stably bound to microtubules– inhibition of anaphase is then alleviated

42
Q

What is the target of SAC signalling pathway?

A

the target of SAC is the APC (which is an E3 ubiquitin ligase)

43
Q

Which sequence does the APC ubiquitylate on it’s target proteins?

A

D-box and/or KEN-box degrons

44
Q

Which cofactors are required for the activation of APC by the SAC signalling pathway?

A

Cdc20 or Cdh1

45
Q

What is the MCC (mitosis checkpoint complex)? When is it formed? what does it consist of? What does MCC do?

A

It is generated by the Spindle assembly checkpoint

formation of MCC is catalysed by unattached kinetochores during prometaphase

MCC comprises Mad2, BubR1, BubR3 and Cdc20

MCC leads to the inhibition of APC

46
Q

when does MCC formation cease? what is the effect?

A

generation of MCC ceases when all the kinetochores have attached to the spindle in metaphase

Cdc20 is hence released from the complex and activates APC which subsequently leads to the ubiquitylation and degradation of securin and CycB

47
Q

What is the effect of degradation of securin by APC?

A

securin is initially bound to separase enzyme which inhibits the activity of the enzyme.
degradation of securin releases the separase which catalyses the cleavage of the of the cohesin ring (at scc1 subunit of the ring); this opens the ring and allows the sister chromatids to be separated

48
Q

What is the effect of degradation of CycB by APC?

A

cyclin B degradation inactivates the Cdk1 which leads to mitotic exit

49
Q

mutations in which proteins of the SAC are common in human cancers?

A

BUB1–(colon cancer)
PLK1
Aurora-A and -B

50
Q

Where does Aurora A localize? What is its basic function?

A

It localizes at the centrosome during interphase and at the mitotic poles and adjacent spindle microtubules during mitosis
Aurora A is associated with centrosome maturation and separation and thereby regulates spindle assembly and stability

51
Q

What is the effect of Aurora A inhibition?

What is the effect of Aurora B inhibition?

A

Aurora A inhibition induces temporarily a mitotic arrest, cells exit from mitosis with multipolar and monopolar spindle formation, leading to apoptosis

Aurora B inhibition induces endoreduplication (replication of genome but no mitosis), chromosome misalignments and polyploidy

52
Q

Mitosis targeting therapies!

A

anti-mitotic drugs trigger a mitotic arrest depending on the SAC
anti-mitotic drugs include–> microtubule poisons, mitotic kinase inhibitors, kinesin inhibitors etc.

this cell arrest is transient and cells exit from mitosis (mitosis slippage) with different fates– proliferation, arrest in interphase or cell death

Drugs that inhibit the SAC (checkpoint abrogation) may have deleterious effects by triggering rapid mitotic exit with subsequent chromosome aberrations

Drugs preventing mitotic exit (e.g. APC inhibitors) result in cell death

53
Q

Mitosis targeting therapies!

A

anti-mitotic drugs trigger a mitotic arrest depending on the SAC
anti-mitotic drugs include–> microtubule poisons, mitotic kinase inhibitors, kinesin inhibitors etc.

this cell arrest is transient and cells exit from mitosis (mitosis slippage) with different fates– proliferation, arrest in interphase or cell death

Drugs that inhibit the SAC (checkpoint abrogation) may have deleterious effects by triggering rapid mitotic exit with subsequent chromosome aberrations

Drugs preventing mitotic exit (e.g. APC inhibitors) result in cell death

MIMS- cell cycle and cancer (5 decks)

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