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Cancer Chromosome Biology > Chromosome Biology > Flashcards

Chromosome Biology Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

What is aneuploidy?

A

a wrong number of chromosomes and most cancer cells show a certain level on aneuploidy within their genome.
Can be screened with spectral karyotyping

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2
Q

How are mitotic chromosomes formed?

A

Condensin 1 and 2 build the scaffold, highly condensed chromatin loops build around it.
Condensin 1 forms larger loops and condensin 2 forms smaller loops within the large ones.
Topoisomerase 2 is also involved in the chromosome structure formation.
Packing ratio 7000 fold on shortest chromosome

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3
Q

Two different types of chromatin

A 
Euchromatin = An open, decondensed form of chromatin. Transcription of genes can only happen when chromatin is in this form.
Heterochromatin = A closed, highly condensed form of chromatin. Repressors and activators are able to convert between the two states.
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4
Q

List the hierarchical organisation of interphase chromatin

A

Chromosome territories > Compartments (euchromatin/heterochromatin) > TADs Topologically associated domains where DNA sequences inside TADs physically interact with each other more frequently than sequences outside.

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5
Q

In interphase, how are chromosome loops formed?

A

Cohesin holds DNA together to form loops. CTCF binds specific CTCF motifs on DNA to define the size of the loops.

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6
Q

How to transcriptional activators / repressors work?

A

They move TADs into different compartments to activate or repress them.

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7
Q

How can the disruption of insulated neighbourhoods activate proto-oncogenes?

A
  • CTCF/Cohesin binding sites can be mutated, causing disorganisation.
  • Breakdown of TAD border leads to deregulation of gene expression. (IDH1 mutation causing methylation in brain tumours). Enhancers can become in close proximity to oncogene promoters.
  • Microdeletions can eliminate boundary sites on insulated neighbourhoods. Causes elevated oncogenic levels and expression of genes normally isolated.
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8
Q

Structure of histones

A

Histones (H2A-H2B & H3-H4) [X2] form the octamer core called the nucleosome.
Histone protein tails stick out of the core and are easily accessible for modifications.

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9
Q

How can histone tails be modified?

A

methylated, acetylated, phosphorylated, ubiquitinated and ribosylated.
Individual modifications to the histones create a histone code that can promote certain outcomes.
- H3 (Me3) at K9 for gene silencing
- H3 (Me3) at K4, (Ac) at K9 for gene expression

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10
Q

What are the features of the histone code?

A

Histone code is an epigenetic regulatory mechanism

  • epigenetic level of coding information – it does not involve DNA but can be inherited.
  • involves writers, readers, erasers and effectors. Mutations = increased oncogenic levels, impacted DNA repair from changes in epigenetic marks or reading them.
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11
Q

4 examples of epigenetic regulation

A
  1. DNA methylation of CpG islands
  2. Non coding RNAs
  3. Histone modifications
  4. Histone variant exchange
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12
Q

How can small drug inhibitors help cancer treatment?

A

Can restore the normal healthy function of histone modifications.
EX - DNMT1 in CMML by Decitabine (FDA)

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13
Q

What is the centromere?

A

A constricted region on a chromosome that joins two sister chromatids
The site where the kinetochore is formed
Allows segregation of sister chromatids

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14
Q

What is the kinetochore?

What are its functions?

A

A multi-protein complex that forms at the centromere
Allows segregation of sister chromatids

  • The site on a chromosome where microtubules of the mitotic spindle attach.
  • Identify and repair incorrect attachments
  • Harness force to generate movement of chromosomes during anaphase.
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15
Q

What is CCAN?

A

Constitutive centromere associated network
Combined with the centromere specific chromatin, creates the CENTROMERE.
Present at all stages of the cell cycle.
Kinetochores are built on this base.
Formed of approximately 20 centromeric proteins, all highly conserved

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16
Q

What is CENP-A (CenH3) and how is it loaded onto chromosomes?

A

CENP-A is a centromeric chromatin marker. CENP-A containing nucleosomes have different features to canonical ones. Generally more condensed. Found using antibody staining.

Newly synthesised histones loaded during S phase
CENP-A replaces H3 in telophase/early G1
Mis18 complex binds centromeres to show HJURP complex where to bind and load the CENP-A.
CATD = specific domain that allows it to be recognised for loading.

17
Q

How is a kinetochore formed?

A

CDK phosphorylates CCAN to allows formation of KC to begin.
Structural core = KMN network (KNL, Mis12, Ndc80 [link to MT] complexes)
KMN forms physical connection between chromosome and spindle. Binding platform for many other regulatory proteins.

18
Q

Difference between the inner and the main centromere?

A 
MAIN = CENP-A loading factors and CCAN
INNER = Cohesins, Aurora B and Shugoshin
19
Q

How are correct spindle-kinetochore attachments regulated?

A

Only correct attachments become locked in space, spindle attached to + end of KC MT.
Regulated by Aurora B complex (chromosome passenger complex) - 4 subunits

20
Q

How does Aurora B work?

A

When the attachment is wrong, there is no poleward force from the microtubule end.
The kinetochore is under low tension, Aurora B is close enough to phosphorylate the Ndc80 complex of the KMN network. Destabilises binding to microtubules.

When the attachment is correct, a tension is created. The outer kinetochore takes the plate containing the KMN network (Ndc80) out of reach of Aurora B so it can no longer phosphorylate it.
The connection between the kinetochore and the microtubules become stable.

21
Q

Members of the aurora family and their connection to disease.

A

A - localised to centrosomes
B - part of the CPC. Segregation and cytokinesis
C - meiosis

Overexpression of all three found in different cancers.
A+B inhibitors lead to cell cycle arrest and apoptosis.

22
Q

What are the 3 types of proteins involved in genome organisation?

A

Topoisomerase IIa - introduces or removes DNA linkages, localised to chromosome axis.
Condensin I and II - both have SMC2 and 4 subunits, but different 3 non-SMC subunits. Depletion = disruption of chromosome structure.
Cohesins - SMC1 and 3. Define chromatin borders with CTCF. Have 2 non-SMC subunits. ATPase for activity.

23
Q

What are the functions of cohesin?

A

Functions in mitosis, meiosis and interphase

  • sister chromatid cohesion
  • repair of DNA breaks
  • organisation of TADs/chromatin loops
  • regulation of transcription during interphase
24
Q

Steps of the cohesin cycle.

A

Loaded onto DNA in G-phase by Scc2
Eco1 acetylates cohesin during S-phase to establish ‘cohesive’ cohesin to hold sister chromatids together.
At G2/M all cohesin is cohesive.
Removed in mitosis

25
Q

How is cohesin removed?

A

Occurs in two waves, allows segregation:

  1. The prophase pathway – mitotic kinases (Wap1, Aurora B kinase) remove 95% of cohesins from the arms of the chromosomes.
  2. The metaphase pathway - Separase destroys the rest of the cohesin at the exact moment of anaphase onset.
26
Q

How is cohesin removal regulated?

A
  1. Shugoshin and PP2A protect centromeric cohesin.
    CPC/Bub1 recruits and localises Sgo1 to centromere.
    Sgo1 binds cohesin and recruits PP2A.
    PP2A counteracts mitotic kinases which phosphorylate and remove cohesin.
  2. Separase activation/inactivation of Cdk1 are needed before anaphase can start.
    SAC activates APC to trigger degradation.
27
Q

What occurs at the spindle assembly checkpoint (SAC)?

A

When the kinetochores are unattached, a STOP signal is generated to inactivate APC.
STOP signal is 4 protein complex called mitotic checkpoint complex (MCC).
When all KCs are correctly attached, MCC is no longer produced and APC is active. Degrades regulatory proteins to activate separase and inactivate Cdk1.

28
Q

How are separase and Cdk1 regulated?

A

Securin inactivates Separase.
Cyclin B activates Cdk1.
When the SAC is satisfied, securin and cyclin B are degraded.
Separase is activated for segregation and Cdk1 is inactivated for mitotic exit.

29
Q

Components of the SAC

A

SAC components are recruited to unattached kinetochores, but not to properly attached ones.
MCC is generated.
Mps1 = kinase responsible for sensing the MT-KC attachment.
Aurora B kinase correct improper attachments. Recuits Mps1.

30
Q

What are cohesin mutations in cancer?

A

Most frequent mutations in STAG1/2/Scc3 - leads to aberrant chromosome segregation.

31
Q

What is CIN?

A

Chromosomal instability = the lack of capacity to maintain the same number of chromosomes from one generation to the next.

32
Q

How are CIN and aneuploidy related / differences.

A 
Aneuploidy = acquired state of the cell 
CIN = a process causes by aneuploidy and can lead to aneuploidy.
33
Q

What are the consequences of aneuploidy?

A
  • leads to up/mis regulation of genes
  • impaired proliferation and metabolism
  • induces chromosomal instability
  • adaptability causing genetic heterogeneity in a population - cancer evolution
34
Q

What are the 4 types of attachments and how does mis-segregation occur?

A
  1. Amphitelic (proper tension, inactive SAC)
  2. Monoteric (no tension, active SAC)
  3. Syntelic (no tension, active SAC)
  4. Merotelic (proper tension, inactive SAC) improper attachment

When the cells are overwhelmed with errors, cells can miss merotelic attachment repairs to cause lagging chromosomes and aneuploidy.

35
Q

5 possible origins of aneuploidy.

A

1 - Impaired SAC - fails to delay anaphase. Segregation occurs with unattached kinetochores.
2 - Impaired cohesion - premature release of cohesin leading to unattached or lagging chromosomes
3 - Supernumerary chromosomes - Multiple centrosomes leads to multipolar spindles. A multipolar anaphase will never occur, but from this a bipolar anaphase will occur with more merotelic attachments than usual.
4 - Error in MT-KC attachments
5 - Problems with cytokinesis

36
Q

What are the different structural variations (SVs) and how were they found?

A

Intrachromosomal SVs - same chromosome
Interchromosomal SVs - exchange between different

SVs come along with numerical aberrations and were revealed through next gen sequencing.

37
Q

What is chromothripsis and how does it occur?

A

When the chromosome is shattered and there are extreme rearrangements when ligated back together.
Leads to cancer genome evolution.

Mis-segregation leads to micronuclei. DNA replication is defective in micronuclei, causing damage until chromothripsis occurs. Then, the rearranged DNA can be incorporated back into the genome leading to cancer development.

38
Q

How can aneuploidy be used in cancer therapeutics?

A

Aneuploidy is a weakness and causes impaired survival.
Inducing CIN to lethal levels to cause cell death.
EX - anti-neoplasia agents to take the aneuploidy past the pre-existing level.

Cancer Chromosome Biology (6 decks)

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