Biology Reference
In-Depth Information
seems reasonable that hINO80 may work both directly and indirectly to
promote repair of DNA DSBs in mammalian cells, and perhaps the relative
contribution of each mechanism varies by cell type and growth conditions.
IV. Perspectives
The importance of the RSC and INO80 chromatin-remodeling complexes
in the DNA damage response has been clearly demonstrated but a number of
questions remain. These two remodelers are not the only ones involved in DNA
repair. Other remodelers shown to contribute to efficient repair and checkpoint
responses in budding yeast include SWI/SNF (localizes to a DSB and remodels
the donor template
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) and SWR1 (important for error-free NHEJ
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). In higher
eukaryotes, the list is even longer and, in addition to INO80 and BAF/PBAF
(SWI/SNF), includes ACF1, TIP60, and WICH. The restoration of chromatin
structure following completion of repair is also likely to require ATP-dependent
chromatin-remodeling complexes, but to date, this has not been studied in any
detail. It seems probable that the full extent of involvement of chromatin
remodeling and the list of complexes involved has not yet been uncovered.
Regulated sequential recruitment of multiple chromatin-remodeling com-
plexes to a DSB occurs, raising the question of why there is so much complexity
if their function is purely to open chromatin to allow access to repair proteins.
It is already apparent that changes in chromatin structure catalyzed by remo-
deling complexes act not only to allow access to repair proteins but also to
facilitate processing and binding of signaling and checkpoint proteins. Differ-
ent remodeling events may be required for different steps of the repair process.
It remains to be explored how the INO80 remodeling event is coordinated with
the rapid changes in chromatin structure catalyzed by RSC that also promote
resection or how these events integrate with the functions of the other remo-
delers recruited to the break. Perhaps INO80 remodeling at a break first
requires the action of RSC, or INO80 may only be required at persistent
breaks where repair has failed to occur.
Alternatively, it could be that not all breaks are processed and remodeled
in the same way. One can envisage breaks formed in heterochromatin or
regions with higher-order chromatin structure having a greater dependency
on chromatin-remodeling complexes in order to open their chromatin than
those in euchromatin or in highly transcribed regions. Similarly, the relative
importance of different complexes may vary with the cell cycle phase either
through changes in expression or through posttranslational modifications and
could even help to channel repair down a particular pathway, for example, HR
versus NHEJ. Different lesions such as UV-induced 6-4 photoproducts and
cyclopyrimidine dimmers (CPDs), alkylated bases, abasic sites, and interstrand
