Genetic integrity was once thought to involve unique DNA stability. We now realize that DNA is incessantly subject to shockingly high levels of damage by endogenous and exogenous toxicants. Thus DNA repair networks are essential to life: they act in every aspect of cell physiology from DNA replication to transcription. Indeed, a critical secret of the double helix structural biology is in its ability to provide an intrinsic means for accurate repair.

DNA damage responses have key human health implications including risk assessment of environmental agents, cancer interventions, and the molecular bases of cancer, aging, and degenerative diseases. Single and double strand breaks in the phosphosugar backbone of DNA occur constantly in every cell. Furthermore chemical modifications of nucleobases by oxidation, deamination, depurination, alkylation or cross-links are common. So the biological outcomes of DNA damage depend dramatically upon repair outcomes. In fact, the typical DNA detection, removal, and replacement repair process forms reactive or miscoding intermediates that are themselves toxic and mutagenic. Consequently, there is strong genetic selection for seamless handoff of repair intermediates and the coordination among competing repair pathways to ensure accurate restoration of DNA structure.

DNA repair processes are therefore prototypical systems to examine how protein structures are connected for the coordination of steps within a pathway or for cooperation among different pathways. Newly emerging results reveal different biological outcomes from a single DNA repair complex. Such distinct outcomes occur through modular and transient interfaces, conformational switching, and interface exchanges. Indeed, repair complexes can manifest an extreme multi-protein allostery in terms of conformational states and long range changes that integrate cellular information and outcomes distinct complexes

This meeting considers the structural biology of the major pathways of DNA repair and their interface with all DNA transactions in cell biology. Topics will stress the involvement of DNA repair complexes in decisions points in cell biology including replication, recombination, and transcription processes. Talks will include the nature of the DNA damage, our understanding of repair detection, signally, and processing mechanisms, and the connections of DNA repair responses and human health.

The structural biology of DNA repair assemblies with their conformations and interactions provides the foundation for a unified understanding of the biochemistry, genetics, and cell biology. Indeed, the structural biology of DNA repair has profound implications for the interpretation of the genetic code, the consequences of DNA mutations in human disease, and the preservation of the species.

Overall, this conference provides a critical opportunity to bring together experts in diverse fields relating to basic mechanisms of DNA repair revealed by the structural biology of the complexes. The outcomes of integrated discussions will be fundamental insights into the challenges and opportunities of DNA repair structures for linking proteins to their biologically relevant states and assemblies.

Tom Blundell and John Tainer