Spectrum Biology - September 2016

Modification of Nucleosome Structure

 A large amount of DNA comes into contact with the spool,

most of it is inaccessible to other DNA-binding proteins,

thereby negating the beneficial effects of these spools.

 Cells use three different mechanisms to address this problem.

These mechanisms are described in the given table.

Different Levels of DNA Organisation in

Eukaryotic Cells

 Eukaryotic cells adopt an additional means for

organising DNA that most prokaryotes do not use,

i.e. they cut their DNA up into several

chromosomes.

 Chromosomes are very large bundles of DNA with

distinctive shapes that change over the course of a

cell’s life.

 During mitosis, these chromosomes condense to

form X-shaped structures. They decondense once

mitosis is complete.

1. Chromatin
   remodeling
   SWI/SNF
   proteins use
   ATP energy to
   move the core
   particle a short
   distance along
   the DNA. This
   makes base
   pair sequence
   free that may
   have been
   buried in the
   core particle.

SWI/SNF

DNA binding proteins

The SWI/SNF proteins slide the core particle, thereby exposing the previously

wrapped DNA to DNA binding proteins. This requires metabolic energy,

DNA is cleaved to ADP and inorganic phosphate (Pi).

SWI/SNF

ATP ADP + Pi

2. Histone
   remodeling
   Histone
   proteins
   are chemically
   modified to
   modify the
   shape of the
   nucleosome.

The exact shape of the tail regions

of the histones is not known, but

they are long enough to project

out of the core particle.

The tail regions likely project

past the DNA double helix,

and are flexible.

When methyl, acetyl or

phosphate groups are

attached to the tails, the

tails change shape,

altering access to the

DNA wrapped around

the core particle. In most

cases, these modifications

restrict access to the

underlying DNA. The actual

shape of the modified

tails is known.

3. DNA
   methylation
   Methyl groups
   are added
   directly to
   the bases
   adenine
   in the DNA.

N

H

N

N

N N

H

CH 3

Methyl adenine Methyl cytosine Methyl guanosine

N

N

CH 3

NH 2

N

N

N N

H

O CH 3

HN 2

Histone remodeling

P Me

Ac

Me

Me

P

Ac

H 3

HB 2

H 4

HA 2

H 2

H 3

Me

Ac

P Me

Chromosomal Instability and Cancer

Chromosomal instability is a hallmark of most solid tumours. Chromosome

missegregation is an important mechanism of tumour adaptation. A direct

consequence of chromosomal instability is an aneuploidy. Many hematopoietic

malignancies were found to be clonally aneuploid. Thus, aneuploidy and

chromosomal instability are interrelated. Recent studies have shown that aneuploidy

and chromosomal instability have independent contributions to tumour evolution and

growth, even while co-existing throughout the tumour’s life-time.

Structure

(a) DNA double helix

(b) Nucleosomes

(‘‘beads-on-a-string”)

(d) Looped domains

5A

(interphase)

5B

(mitosis/

meiosis

only)

(e) Folded/twisted

loop domains

(f) Highly condensed,

duplicated

chromosome

The five different levels of DNA organisation in eukaryotic cells

DNA

packing level

2 nm

10 nm

30 nm

300 nm

700 nm

1400 nm

4

Euchromatin

heterochromatin

(eukaryotes only)

2

1

123

(c) 30 to 40-nm

chromatin fibre

3