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cross-links are also likely to require chromatin remodeling for their repair and
could have differing requirements for specific remodeling complexes. It seems
to be the case that chromatin remodelers have both redundant and nonover-
lapping roles in DNA repair.
Chromatin-remodeling complexes contain many subunits with chromatin-
binding domains such as chromodomains, bromodomains, and BAH domains.
In concert with posttranslational modifications of histones that occur as part of
the DNA damage response, this provides a means to target chromatin-
remodeling complexes to the site of damage in a location- and timing-specific
manner. Binding of these targeting domains to chromatin modifications is
generally of low affinity but may contribute to retention of remodelers, if not
their initial recruitment. Equally, the chromatin-remodeling complexes them-
selves could be posttranslationally modified and this has the potential to alter
their activity; indeed, phosphorylation of the Ies4 subunit of INO80 by Mec1/
Tel1 has been identified and Rsc2 has been found to be sumoylated.
121
To date,
the specific functions of many of the individual subunits of remodeling com-
plexes have yet to be elucidated. It may be these subsidiary subunits that
provide specificity and regulation.
One of the challenges for the future is to integrate the growing numbers of
DNA damage chromatin modifications and the multiple chromatin-remodeling
complexes involved in the DNA damage response to generate a mechanistic
picture of their function in DNA repair. As chromatin-remodeling complexes
are involved in many other processes in the cell including transcription and
replication, the interplay of these cellular activities with the DNA damage
response must be taken into consideration. There is a high degree of conser-
vation between yeast and human remodelers and so many of the findings in
S. cerevisiae
are likely to be applicable to human cells. While the mechanism is
not entirely known, it is clear that genes encoding subunits of chromatin-
remodeling complexes are frequently mutated or misregulated in cancer
(e.g., Ref.
122
). As a result, this family of enzymes may provide diagnostic
and therapeutic targets for cancer and genome instability disorders.
Acknowledgments
This work was supported by Cancer Research UK (CEAC7905/A8265). We apologize to the
authors whose work we have not cited due to limitations in the size and scope of the review.
References
1. Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: production, fidelity of
repair, and induction of cancer.
Proc Natl Acad Sci USA
2003;
100
:12871-6.
