Overview
Purpose The rejoining of fragmented nuclear DNA caused by ionizing radiation may lead to lethal chromosome rearrangements, such as rings or dicentrics. The clinically useful linear quadratic relationship between dose and cell survival has been interpreted as the generation of lethal lesions secondary to damage occurring in two separate chromosomes simultaneously (a component), or as potentially repairable separate events (b component). Here, the generation of such lesions is discussed, synthesizing existing knowledge with new insights gleaned from spatial proximity data made possible by high-throughput sequencing of chromosome conformation capture experiments. Over a range of several Mbp, the linear DNA strand is organized as a fractal globule generating multiple sites of contact that may facilitate deletions or inversions if the points of contact are damaged. On a larger scale, transcriptionally active euchromatin occupies a physically identifiable space separate from inactive areas and is preferentially susceptible to free radical attack after irradiation. Specific transcriptional programs link genomic locations within that space, potentially enhancing their interaction if subject to simultaneous fragmentation by a single radiation event. Conclusions High throughput spatial analysis of the factors that control chromosome proximity has the potential to better describe the formation of the lethal chromosome aberrations that kill irradiated cells.
Overview source: Curated paper metadata.
Methods and contributions
Read the source for the full argument, qualifications, and evidence.
Findings and contributions
- The review describes the linear DNA strand over several Mbp as a fractal globule whose multiple contact sites may facilitate deletions or inversions if damaged.
- Transcriptionally active euchromatin occupies a distinct space and is preferentially susceptible to free radical attack, which may favor rearrangements within that compartment.
- The authors argue that the contribution of DNA repair programs to radiation lethality may depend on the spatial organization of the breaks, not just rejoining ability.
- They propose that, if pre-irradiation chromatin state biases rejoining, transcriptome-modulating tools (e.g. RNAi, microRNA) could be an unexplored route to radiosensitization.
- The review concludes that answering its open questions will likely require single-cell Hi-C merged with aberration analysis in irradiated material.
Methods
- Review of cell-kill models (target theory, LQ, dual radiation action) — Surveys Lea's target theory, Chadwick-Leenhouts molecular theory, and Kellerer-Rossi dual radiation action as frameworks for radiation-induced lethal lesions.
- Synthesis of Hi-C / chromosome conformation capture proximity data — Interprets published genome-wide 3C/Hi-C contact data to relate chromatin spatial organization to formation of radiation-induced rearrangements.
- Cross-reading Hi-C contacts with transcription and translocation data — Draws on studies linking Hi-C compartments to transcriptional activity and to clinically relevant translocation partner proximity.
Summary sources: Paper metadata and evidence · Extracted source text.
PDF downloads
Archived files available directly from this site.
- 2016_NuclearStructure.pdf PDF · 1.24 MiB · extracted-text source
Citation
Citation metadata follows the unified bibliography.
Catalog details and resources
Related in Genetics & Biomedical
Other catalogued works in the same domain.