TABLE 2.

Multiple levels of protection against DSBs.

Compaction level	Structural factors that suppress reactions between DNA and reactive oxygen species (ROS).	Structural factors that suppress formation of DSB during replication, transcription, or attempted base excision repair (BER).
DNA alone (and DNA- associated small molecules)	Narrow minor grooves (created by either sequence context or DNA bending) limit access by ROS. Spermine and similar small molecules may partially displace water from DNA, reducing the number of molecules that can be transformed by IR into ROS. They also provide reactive moieties that may help quench local ROS.	Local, sequence-directed bending of DNA can influence the relative rates of lesion discovery and repair at sites containing multiple clustered damages. In principle, this might reduce the probability of DSB formation from near-simultaneous generation of nicked or gapped repair intermediates in opposing DNA strands.
Nucleosome	Minor groove narrowing imposed by wrapping of DNA about the histone octamer, and histones themselves partially limit access to ROS reactive moieties in DNA; histones also provide reactive moieties that may help quench local ROS.	As depicted in Figure 4, nucleosomes substantially restrict the fraction of clustered oxidative lesions that can be transformed into DSBs during attempted BER.
Hetero- chromatic regions & higher order chromatin structures*	Linker histones and other chromatin- associated proteins limit nucleosome mobility, increasing the total fraction of DNA protected by histones. Higher order coiling (particularly the ‘zig- zag’ or crossed-linker configurations) may reduce access of ROS to linker DNA.	Linker histones and other chromatin- associated proteins that limit nucleosome mobility may partially suppress BER-dependent formation of DSBs while higher order coiling may abolish BER altogether. Transcription-associated formation of DSBs would be similarly affected.

^*While higher order chromatin compaction generally confers greater protection from DSBs, high LET radiation creates non-random damage within these structures, potentially creating more deleterious damage than their decondensed counterparts.