Biomedical Engineering Reference
In-Depth Information
easily explained by rapid chromatin decondensation around heterochromatic DSBs,
which is necessary either to allow a repair competent environment (increase the
accessibility of huge repair complexes to damaged DNA) at the original sites of
DSB lesions or to enable movement of DSBs into nuclear subcompartments that are
more convenient locations for repair processes to occur [discussed in
135
].
Both these hypotheses are not mutually exclusive and are not unprecedented
in cellular biology: The potential movement into repair factories may be similar
to the dynamic associations of genes in transcription factories, as discussed in
the next section (
20.4.5
). On the other hand, it is also generally accepted that the
condensed nature of heterochromatin poses a barrier to enzymes and other proteins
that operate on DNA [
223
] and it must relax to allow transcription and replication
[
224
-
226
]; therefore, chromatin decondensation may also be expected at the sites
of heterochromatic DSBs. Indeed, epigenetic histone modifications typical for open
euchromatin like increased H4K5 acetylation, decreased H3K9 dimethylation, and
other modifications were observed at the sites of the DSBs almost immediately after
their induction [
198
]. In accordance, as already discussed, ATM activates repair
proteins that mediate chromatin decondensation such as KAP-1 (KRAB-associated
protein 1, also known as TIF1b, TRIM28 or KRIP-1 [
68
,
227
,
228
]); importantly,
this ATM activity is necessary only for the repair of heterochromatic DSBs. In
support of this, dissociation of Heterochromatin protein 1 (HP1 [
215
,
216
]) from
affected heterochromatin domains was observed soon after irradiation [
201
,
217
-
220
]. Moreover, in addition to local chromatin decondensation observed at the
sites of lesions, global pan-nuclear decondensation initiated by DSB damage was
described by Ziv et al. [
227
]. Finally, ATM initiates a complex DNA damage
response that includes cell cycle arrest, which provides additional time for repair
of heterochromatic breaks that can only be processed slowly.
Chromatin structure is, therefore, an important determinant of the initiation
phase of DSB repair. Since, in addition to ATM, a lot of other proteins like
”
H2AX, MDC1, 53BP1, RNF8, RNF168 and Artemis are specifically required
only for processing of DSBs in heterochromatin [
70
,
228
], the above results can be
interpreted as adaptive modification of NHEJ to problematic chromatin structure
6
.
All together, DSB repair in heterochromatin seems to be slower, less efficient, and
is potentially associated with increased formation of chromosomal translocations as
discussed in Sec.
20.4.5
.
Higher-order chromatin structure, however, also plays an important role in
the terminal phase of DSB repair, as already discussed in the Sec.
20.4.3
in
the context of persistent
H2AX foci. Since gene transcription is regulated by
chromatin structure that is determined by an epigenetic code (Sec.
20.4.2
), the
original chromatin status must be somehow reconstructed along megabase-sized
”
6
Multiple complex DSBs introduced into DNA by densely ionizing radiation [
229
,
230
] also require
additional extensive processing of damaged DNA ends as compared to repair of simple DSBs
induced by low-LET IR [
231
-
233
]. Both higher-order chromatin structure and DSB characteristics
thus may determine individual steps of the repair mechanism
