This proposal requests partial support for the FASEB Summer Research Conference on Dynamic DNA Structures in Biology, to be held at Itasca, Illinois, July 20-25, 2014. For decades after its discovery, DNA was believed to be a rigid, right-handed double helix. This belief was shaken by the findings that DNA structure is much more dynamic. In fact, DNA can form an enormous variety of conformations, including cruciform-like, left-handed helixes, three and four stranded helices, slip-stranded configurations, etc. Most importantly, repetitive DNA sequences, which are overrepresented in genomic DNA, are particularly prone to structural transitions. Transient denaturation of the double helix, which promotes these dynamic transitions in DNA structure, occurs during all major DNA transactions, including replication, transcription, and recombination. Studies conducted in many labs worldwide have confirmed that structure-prone DNA sequences are central to the normal functioning of the genome, and they are also responsible for its occasional malfunctioning. One particularly striking example is the discovery that expansions of structure-prone DNA repeats leads to more than thirty hereditary neurological and developmental diseases in humans. Dynamic DNA structures are also associated with translocations observed in many human cancers. They are also involved in regular DNA processes including transcriptional activation, regulation of antigenic switching, and DNA recombination essential to the immune response. In an unexpected twist, these DNA structures appeared to be invaluable for nanotechnology, where their unusual physical properties find numerous applications. The long-term objective of this Conference is to enhance our understanding of how dynamic DNA structures form, how they are resolved, how they contribute to normal genetic processes and to pathological developments, including genetic disease, cancer and aging.
The specific aims are to explore current understanding, to identify new avenues of investigation, to define novel mechanisms that promote formation and resolution of dynamic DNA structures and, thus, offer therapeutic targets for maintenance of genomic integrity, to stimulate collaborations, and to foster the long-term development of this area by promoting participation of junior scientists. To that end, we will convene 33 speakers and discussion leaders and more than 100 participants for five intense and highly interactive days of science. The program will include a keynote and eight sessions, entitled: (1) Expandable DNA Repeats and Human Disease;(2) Chromosomal Fragility;(3) Transcription and Its Collisions with Replication;(4) Repeat-Induced Mutagenesis;(5) DNA Gymnastics in Recombination;(6) Recurrent and Non- Recurrent Chromosomal Rearrangements in Human Disease;(7) G4 DNA in the Genome;(8) Nano-DNA Structures. Each session will include two-to-four short talks by students, postdocs, and newly independent investigators, and three afternoon poster sessions will permit the attendees to present and discuss their newest results. The significance of this conference is that it uniquely propels research by bringing together investigators with a common focus but varied backgrounds, expertise and experimental approaches, thus, enabling research to progress more rapidly. The biomedical relatedness is in the importance of dynamic DNA structures in normal nuclear functions and as the cause of genomic pathologies that result in genetic disease.
DNA gymnastics is at heart of genome functioning in health and disease. As we now know, DNA can adopt many dynamic structures that play pivotal roles in normal genetic processes. On the flip side, unwarranted formation of these structures during major DNA transactions can cause genomic pathologies that result in hereditary diseases, cancer or aging. This conference will promote understanding of how dynamic DNA structures form, resolve and function, which is key to understanding the origin of human disease as well as to developing new diagnostics and therapeutics.