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Cancer & The Cell Cycle > Lecture 5 - Nuclear organisation > Flashcards

Lecture 5 - Nuclear organisation Flashcards

1
Q

How can nuclei change in cancer?

A
  • Shape and margin irregularity
  • changes to chromatin compaction/texture
  • altered nucleoli
  • variations in size
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2
Q

When is heterochromatin replicated?

A

late in S phase

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3
Q

When is euchromatin replicated?

A

Usually earlier in S phase

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4
Q

Why is euchromatin replicated early in S phase?

A

So the cell has 2 copied of it for longer

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5
Q

What is a SARs or MARs?

A

Scaffold/Matrix Attachment Regions

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6
Q

What do some people believe about the nuclear matrix?

A

There is an interconnecting network extending from the nuclear matrix through the cytoskeleton to the extracellular matrix

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7
Q

Why is it difficult to see the ‘interconnecting network’?

A

Usually studied in cultured cells which are different from cells in tissues

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8
Q

How is chromatin organised?

A

In loop attachments formed by periodic attachment to the nuclear matrix MARs and SARs

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9
Q

What happens at the base of the loops of chromatin?

A

Site of assembly of molecular machines involved in txn, splicing and DNA replication

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10
Q

Why is it good that everything happens at the loops of chromatin?

A

Regulatory elements can all come together there

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11
Q

How can the loops of chromatin cause disease?

A
  • SATB1 (special AT-rich binding protein) is normally at loop bases
  • Loss deregulates expression oof 2% of genes
  • In KO genes move from loop from base
  • Overexpression linked with aggressive breast and prostate cancer
  • Shows importance of spatial arrangement
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12
Q

What are nucleoli?

A

Sites of ribosome synthesis

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13
Q

What is in the nucleus?

A

Chromatin occupies 35% of volume

Matrix occupies 10%

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14
Q

How is chromatin organised in interphase?

A

Distinct chromosomal bands segregate into different regions giving rise to chromosome territories.
Resulting in establishment of distinct high order genome compartments with functionally distinct chromatin fractions

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15
Q

What can you see when you differentially fluorescently label 2 chromosomes?

A

They move to different parts of the nucleus

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16
Q

How do you perform chromatin conformation capture (3C)?

A
  • Use a chemical cross linker to make interacts between chromatin and protein assembly
  • Digest chromatin into fragments
  • Elute anything not cross linked
  • Ligate generating an artificial DNA strand
  • Analyse and look at frequency of two regions occurring together
17
Q

What is 4C?

A

3C but in different time frames

18
Q

What are common in leukemias and lymphomas that can be cured by chemo?

A

Balanced translocations

19
Q

What are unbalanced rearrangements?

A

Common in solid tumours and are associated with more disorganisation and are difficult to cure

20
Q

What are the two models of order of chromatin?

A

Deterministic and self-organisation

21
Q

What is the deterministic model of chromatin?

A
  • Structural evidence and adapter proteins keep everything together
22
Q

What is the self-organisation model of chromatin?

A

Active regions and silenced regions between chromosomes

23
Q

What does a stem cell require in terms of chromatin?

A

Access to all genes

24
Q

What does a differentiating cell require in terms of chromatin?

A

Establishing order, long range interactions, lineage specific gene expression

25
Q

What does a terminally differentiated cell require in terms of chromatin?

A

Long term functional specialisation

26
Q

What did Coverley do with stem cells?

A
  • Took stem cells and differentiated cells that had been induced from same cell line
  • Added enzymes that digest chromatin to see the proteins bound to (left behind) the nuclear matrix (NC bound)
  • Did this with Cyclin E
27
Q

What results did Coverley get?

A
  • In stem cell cyclin E is easy to extract

- In differentiated cell cyclin E shifted onto the NC

28
Q

What is the implication of Coverley’s result?

A

Cyclin E’s function transitioned from not on the matrix to the matrix

29
Q

What else did Coverley do with cyclin E and what was the result?

A

Tested in cancer cells

Cyclin E was not recruited onto nuclear matrix (cancer cell has no underlying architecture)

30
Q

How can you find how many anchor points there are?

A
  • Solubise nuclear membrane
  • Extract histones
  • Relieve supercoils
  • DNA spreads into a halo only anchored at loop bases (S/MARs)
31
Q

What features of nuclear morphology in cancer be used as a basis for diagnosis?

A
  • Measure of nuclear and tissue disorganisation

- Predictor of aggressiveness

32
Q

What can destabilisation of nuclear order facilitate?

A

Accumulation of other changes (genetic/epigenetic)

Cancer & The Cell Cycle (8 decks)

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