January 19 2010

Dicer shuttles to nucleus and accumulates to form heterochromatin

Scientists from the Friedrich Miescher Institute for Biomedical Research of the Novartis Research Foundation have solved a yeast Dicer riddle. In a publication in Developmental Cell, they demonstrate the nuclear localization of Dicer in fission yeast, thereby linking an important Dicer function to its site of action. They further elucidated a novel cytoplasm-nucleus shuttling process for Dicer that may also be relevant for other organisms.

The protein called Dicer, which is an enzyme crucial for the maturation of a recently discovered player in gene control, namely small double-stranded RNAs, has puzzled the scientific community for several years. How can Dicer, which plays a crucial role in the nucleus of the cell, carry out this activity when it is only found in the cytoplasm. In other words, how can a suspect be the murderer if he was never at the crime scene?

A study published in the latest issue of Developmental Cell by the group of Marc Bühler of the Friedrich Miescher Institute for Biomedical Research resolves this confusing observation.

In their experiments with the simple eukaryotic model organism, fission yeast, Bühler and colleagues have shown that Dicer actually shuttles between the cytoplasm and the nucleus. The shuttling is mediated by a domain on the Dicer protein called "double stranded RNA binding domain" (dsRBD). In both locations, Dicer is involved in RNA interference by cutting long double-stranded RNA species into short RNA fragments, so called siRNAs. By doing so, this enzyme regulates gene expression and concomitantly development.

Yeast Dicer convicted of nuclear localization
A characteristic of fission yeast is that siRNAs and, therefore, also Dicer are crucial to the assembly and silencing of heterochromatin in the nucleus. During this process, large stretches of chromosomes become inactive, rendering genes in those regions inaccessible for RNA transcription. In accordance with these functional observations, the FMI scientists have now shown, in a sophisticated set of experiments, that Dicer is in fact present predominantly in the nucleus. To follow-up on the previous analogy, they have demonstrated using refined methods the presence of the suspect at the crime scene.

Finally, Bühler and his team discovered that a small part of the Dicer protein, which they call "C33", controls its retention in the nucleus. In the absence of C33, Dicer accumulates in the cytoplasm, the formation of heterochromatin is impaired and the protein acts promiscuously.

Evolutionary implications beyond fission yeast
Dicer is a conserved protein also present in higher organisms and with comparable functions. In humans, the Dicer dsRBD domain is not followed by a C33-like motif. As the fission yeast Dicer variant without C33, human Dicer localizes predominantly in the cytoplasm. This raises the interesting question of whether human Dicer also shuttles and whether it has additional activities in the nucleus of human cells.

RNA interference
After a series of initial observations in plants, Craig C. Mello and Andrew Fire were the first in 1998 to describe RNA interference or RNAi as a process in which double-stranded RNA silences targeted genes. Since then, understanding of the process has increased and RNA interference describes all of the processes in a living cell that control gene expression through different kinds of RNA species.
In RNAi, small RNA molecules interact specifically with other RNAs and increase or decrease their activity, e.g. by preventing protein production from mRNA. Central to RNAi is a protein called Dicer. This processes long double-stranded RNA molecules to short approx. 20-nt-long fragments. The two short strands dissociate and, based on its nucleotide sequence, one of the strands interacts with other RNAs.

On Marc Bühler
Marc Bühler is a group leader at the Friedrich Miescher Institute for Biomedical Research and holds a Swiss National Science Foundation Professorship. His research focuses on the role of non-coding RNAs in chromatin-dependent gene regulation.
» More about Marc Bühler's group

About this site2018 © FMI Basel Switzerland