10
Chromosome Organization within the Nucleus
For example, recombination frequently in-
volves an interaction between sites on
two entirely different chromosomes. An-
other example is transvection, in which a
promoter on one chromosome can drive
transcription of a coding region on an-
other chromosome. These interactions do
not occur at a distance, but instead require
the interacting sites to move into close
physical proximity. If the organization of
genes in the nucleus is nonrandom, then
we can predict that the ability of genes to
interact with each other is likewise non-
random. It is veri±ed experimentally that
interactions between different loci during
recombination and DNA break repair is
highly nonrandom. As an obvious exam-
ple, corresponding loci on homologous
chromosomes will be expected to occupy
similar regions of the nucleus. Similarly,
nucleolar loci are more likely to interact be-
cause they are nonrandomly close together
from the outset.
The strong influence that nuclear ar-
chitecture can have on chromosome in-
teractions can be best seen during the
establishment of somatic homolog pair-
ing, which is best known in
Drosophila
but also occurs sporadically in humans
and yeast. An analysis of initiation of so-
matic pairing in
Drosophila
showed that
the loci that paired ±rst tended to start
out close to each other within the nu-
cleus, while loci that started out far apart
tended to pair later. In fact, the pair-
ing could be modeled precisely assuming
that chromatin motion was driven by con-
strained diffusion and taking into account
the known nuclear architecture in the
Drosophila
embryo. Thus, as suggested
by the studies of Robertsonian translo-
cations, it appears that position within
the nucleus plays an important determi-
native role in interactions between chro-
mosomes.
We
can
therefore
propose
a
gen-
eral
model:
because
chromatin
diffu-
sion is constrained to a small subre-
gion of the nucleus, only loci whose
regions of con±nement overlap will be
able to interact. Loci that start out far
apart will be prevented from interact-
ing, since their regions of con±nement
dono
to
v
e
r
l
ap
,soth
a
tph
y
s
i
c
a
lcon
t
a
c
t
is impossible. Thus, the relative posi-
tions between loci, as dictated by the
nuclear architecture, can play a decisive
role in determining which interactions
can occur.
6.2
Robertsonian Translocations
Robertsonian translocations, spontaneous
reciprocal translocations of whole chro-
mosome
arms,
provide
an
illustrative
example of the influence that nuclear or-
ganization might have on chromosome
interactions. The distribution of break-
points in such Robertsonian translocations
is highly nonrandom, such that translo-
cations in which both breakpoints occur
on acrocentric chromosomes containing
nucleolar organizing regions (NORs) are
highly favored. Since cells generally have
just a single nucleolus, chromosomes
with an NOR will tend to be nonran-
domly close in the nucleus, thus biasing
the distribution of recombination break-
points.
6.3
Chromosome Rearrangements in Cancer
Perhaps the most important instance of
nuclear architecture influencing chromo-
some rearrangements occurs in chromo-
some translocations that lead to leukemia.
A translocation between the BCR and ABL
loci on chromosomes 22 and 9 gives rise
previous page 1330 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1332 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off