Histochem Cell Biol (2008) 129:5–11 DOI 10.1007/s00418-007-0355-x R E V I E W Physiological importance of RNA and protein mobility in the cell nucleus Tom Misteli Accepted: 27 October 2007 / Published online: 10 November 2007 © Springer-Verlag 2007 Abstract TraYcking of proteins and RNAs is essential for cellular function and homeostasis. While it has long been appreciated that proteins and RNAs move within cells, only recently has it become possible to visualize traYcking events in vivo. Analysis of protein and RNA motion within the cell nucleus have been particularly intriguing as they have revealed an unanticipated degree of dynamics within the organelle. These methods have revealed that the intra- nuclear traYcking occurs largely by energy-independent mechanisms and is driven by diVusion. RNA molecules and non-DNA binding proteins undergo constrained diVusion, largely limited by the spatial constraint imposed by chro- matin, and chromatin binding proteins move by a stop-and- go mechanism where their free diVusion is interrupted by random association with the chromatin Wber. The ability and mode of motion of proteins and RNAs has implications for how they Wnd nuclear targets on chromatin and in nuclear subcompartments and how macromolecular com- plexes are assembled in vivo. Most importantly, the dynamic nature of proteins and RNAs is emerging as a means to control physiological cellular responses and path- ways. Keywords Nuclear architecture · Dynamics · DiVusion · RNA T. Misteli (&) National Cancer Institute, National Institutes of Health, 41 Library Drive, Bethesda, MD 20892, USA e-mail: mistelit@mail.nih.gov Introduction It is an irony of science that the discovery of fundamental principles is often delayed. A case in point is the cell bio- logical investigation of the cell nucleus. The nucleus is arguably the functionally most prominent cellular orga- nelle as it houses the vast majority of the genetic informa- tion and is the exclusive site of essential processes including transcription, RNA processing, replication and DNA repair. Yet, our understanding of how the nucleus is organized and how nuclear architecture contributes to cel- lular function is only now emerging and still lags behind that of most other cellular compartments. Fortunately, pioneering studies over the past decade have uncovered several of the fundamental principles which determine nuclear architecture and function (Lanctot et al. 2007; Misteli 2001; Spector 2003). These studies have revealed the presence of distinct structural elements, particularly lamin proteins and possibly short actin Wlaments, within the nucleus and they have led to the identiWcation of a large number of distinct nuclear subcompartments in which speciWc nuclear functions, such as the synthesis and processing of ribosomal RNA in the nucleolus, occur (Burke and Stewart 2006; Gruenbaum et al. 2005; Hand- werger and Gall 2006; Hernandez-Verdun 2006; Lamond and Sleeman 2003) (Fig. 1a). In addition, it has become clear that the genome is non-randomly organized within the spatial conWnes of the nucleus with speciWc chromo- somes and genes preferentially localizing to speciWc sites (Lanctot et al. 2007; Meaburn and Misteli 2007) (Fig. 1b, c). These observations paint a picture of a highly complex and heterogeneous cell nucleus. They also indicate that some properties of the nucleus are counterintuitive. For example, despite the requirement to accommodate »2 m of DNA within the cell nucleus of a diameter of typically 123