Regulating gene expression with light- activated oligonucleotides XinJing Tang and Ivan J. Dmochowski* DOI: 10.1039/b614349k Since the development of light-responsive amino acids, the activity of numerous biomolecules has been photomodulated in biochemical, biophysical, and cellular assays. Biological problems of even greater complexity motivate the development of quantitative methods for controlling gene activity with high spatial and temporal resolution, using light as an external trigger. Photoresponsive DNA and RNA oligonucleotides would optimally serve this purpose, but have proven difficult to expand from proofs-of-concept to in vivo experiments. Until recently, the development of this technology was limited by the synthesis of oligonucleotides whose function could be significantly modulated with near-UV light. New synthetic protocols and strategies for both up- and down-regulating gene activity finally make it possible to address biological considerations. In the near future, we can expect photoresponsive DNA and RNA molecules that are relatively non-toxic, nuclease-resistant, and maintain their specificity and activity in vivo. Quantitative, laser-initiated methods for controlling DNA and RNA function will illuminate new areas in cell and developmental biology. 1. Introduction In nature, relatively simple photochemi- cal processes often accomplish complex biological tasks. For example, the visual process by which we are reading this article is initiated in the retina by the 7-transmembrane protein, rhodopsin. 1–3 This G-protein-coupled receptor (GPCR) adopts an inactive form when covalently bound to 11-cis-retinal (Fig. 1), which prevents binding to peripheral membrane proteins, including the heterotrimeric G protein transducin. In this ‘‘caged’’ state, rhodopsin is transiently blocked from performing its biological function. Absorption of a photon induces the rapid (200 fs) iso- merization of 11-cis-retinylidene to the all-trans-retinylidene, and triggers a con- formational change in rhodopsin that activates transducin. The subsequent Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA. E-mail: ivandmo@sas.upenn.edu; Fax: +1 215-898-2037; Tel: +1 215-898-6459 XinJing Tang graduated in 1997 with a B.Sc. degree in Chemistry from ShanDong University in China and received a Ph.D. degree in 2002 from the Technical Institute of Physics and Chemistry, the Chinese Academy of Sciences. His the- sis work focused on the synth- esis and two-photon absorption characteristics of novel organic chromophores. In 2003, he joined Dmochowski’s group as a postdoctoral associate, where he has synthesized and charac- terized new photosensitive DNA and RNA oligonucleotides and studied their biochemical and biological activity. Ivan Dmochowski was born in 1973 and raised in Falmouth, Massachusetts. Growing up next to valuable marine resources and wooded conservation lands instilled in him a love of the natural world. He attended Harvard College, where he made self- assembled monolayers in the Whitesides lab, and graduated with a B.A. degree in Chemistry in 1994. Ivan spent a year synthe- sizing liquid crystalline materi- als in Mainz, Germany with Helmut Ringsdorf and subse- quently attended graduate school at the California Institute of Technology. Under the guidance of Harry Gray and Jay Winkler, he developed ruthenium photosensitizers for the rapid delivery of electrons and holes to the buried heme of cytochrome P450, which led to a Ph.D. degree in 2000. Ivan joined Scott Fraser’s lab, also at Caltech, where he quantified fluorescent proteins in living sea urchin embryos as a Helen Hay Whitney postdoctoral scholar. In 2003 he started as an assistant professor at the University of Pennsylvania, where he has been working on several projects at the crossroads of Chemistry, Biology, and Materials Science. He has been recognized for this work through a Camille and Henry Dreyfus New Faculty Award and a CAREER award from the National Science Foundation. XinJing Tang Ivan J. Dmochowski HIGHLIGHT www.rsc.org/molecularbiosystems | Molecular BioSystems 100 | Mol. BioSyst., 2007, 3, 100–110 This journal is ß The Royal Society of Chemistry 2007