Biophysical Society Thematic Meeting| Santa Cruz 2018

Genome Biophysics: Integrating Genomics and Biophysics to Understand Structural and Functional Aspects of Genomes

Monday Speaker Abstracts

RNA-DNA Hybrids Promote the Expansion of Friedreich's Ataxia (GAA)n Repeats via Break-induced Replication

Sergei Mirkin Tufts University, USA

No Abstract

The Regulatory Roles of DNA Topology and Conformation in Mammalian Gene Expression David L Levens 1 1 National Cancer Institute, Laboratory of Pathology, CCR, Bethesda, Maryland, United States As a undimensional matrix, DNA encodes RNA and the cis-elements that bind gene regulatory proteins to direct transcription and replication. Via these bound factors, DNA sequence also instructs the 3-d folding of the genome. Beyond this static coding by DNA sequence, the double helix undergoes dynamic changes in structure and topology in response to applied mechanical forces. The torque that untwists DNA enabling the bases to serve as a template during transcription and replication, is dynamically propagated through the DNA fiber. Eventually these dynamic supercoils must be accommodated by stress absorbing alternative conformations of DNA and chromatin, dissipated by transmission to remote regions or off DNA ends (telomeres or breaks), or removed by the action of topoisomerases. Melting of DNA at susceptible sequences licenses the formation of non-B DNA structures and absorbs torsional stress. These alternative structures in turn, can modify gene activity by binding structure and/or sequence- selective single-stranded DNA binding proteins, such as the Far Upstream Element, that interact with the transcription machinery, or by controlling chromatin structure via positioned nucleosomes or modifying the elastic moduli of chromatin. Thus, torsional stress is not merely a by-product of genetic processes, but has the capacity via mechanical feedback to regulate those same processes. In turn the transcription machinery and transcription factors directly modify topoisomerase activity to tune torsional stress that on the one hand may impedes or even arrests transcriptional elongation, but that also may encourage DNA melting. For example, both RNA polymerase and the general amplifier of transcription MYC, also stimulate topoisomerase 1 to diminish the dynamic supercoils that otherwise would oppose transcription elongation.

9