Repair of DNA Double-Strand Breaks - Radiation Damage in Biomolecular Systems - page 338

influence the probability of translocations between the particular chromosomes
[reviewed 135 ] and how can nuclear environment modify expression profiles of the
translocated chromosomal parts, e.g . as a result of their heterochromatinization after
translocation to heterochromatic nuclear domains.
Similar rules of organization apply also for chromatin inside the chromosomal
territories [ 153 , 154 , 171 , 172 ]. Genetic information is not distributed homoge-
neously along the DNA molecule; highly expressed genes frequently form clusters
named RIDGEs (Regions of Increased Gene Expression) and silent genes form
clusters named antiRIDGEs [ 159 , 160 ]. Both RIDGEs and antiRIDGEs are spread
nonrandomly through the human genome, forming chromosomes with high, middle
and low levels of overall transcription. To exert their functions, chromatin in
RIDGEs is more decondensed than that in antiRIDGEs, which allows better
access of transcription machinery (and other proteins) to DNA. Conversely, the
condensed chromatin of antiRIDGEs contributes to gene silencing [reviewed,
e.g ., in 173 ].
These structural differences of chromatin are dictated by covalent posttransla-
tional modifications of histones (methylation, acetylation, ubiquitination, phospho-
rylation, etc.) and DNA methylation [ 148 , 174 - 176 ]. Precise positioning of different
combinations of histone modifications throughout the genome constitutes an epi-
genetic “histone code” [reviews 148 , 176 - 178 ] that strictly regulates binding of
additional regulatory and effector proteins to the particular DNA loci. For example,
heterochromatin binding protein 1 (HP1) is required for heterochromatin formation
and specifically binds, by its chromodomain, to the histone H3 dimethylated on the
lysine 9 (dimetH3K9) in DNA loci that should be genetically silenced [ 178 , 179 ].
Conversely, trimethylated histone H3 on the lysine 4 (trimetH3K4) attracts proteins
associated with gene activation (see reviews, [ 180 - 182 ]). Histone modifications
are hereditary and can be reversed by specific enzymes or histone replacement.
This histone code can thus facilitate regulation of local chromatin structure and
expression profiles during development, cell differentiation, replication, and DNA
damage responses or other cellular stresses [ 180 , 181 ].
In three-dimensional space, the nonrandom distribution of active and inactive
DNA loci within the genome, as evidenced by specific epigenetic modifications,
results in the formation of structurally and functionally distinct subchromosomal
domains. Active regions of the chromosome may protrude from their subdomains
andevenfromCHTs[ 183 , 184 ], which allows some dynamic intermingling
of chromatin such as spatial colocalization of several (coregulated) genes in
transcription factories [ 185 - 188 ] or interactions between transcription enhancers
and gene promoters [ 189 ]. On the other hand, long-range pan-nuclear movement
of undamaged chromatin has been rarely reported [ 190 - 193 ]. Therefore, the
nucleus does not have either random structure (formerly liken to a cap of soup
with randomly swimming DNA “noodles”) or rigid, deterministic organization,
but it has a dynamic higher-order chromatin architecture necessary for nuclear
functions.