The virtues of self-control
In all cells patterns of gene activity must be strictly controlled. Too much or too little of a given gene product can be deleterious or even lethal. Higher organisms face a further problem. Their cells generally contain two copies of each gene, as their genomes are made up of two sets of chromosomes, one inherited from each parent. However, most organisms also possess specialized sex chromosomes, which are differentially distributed between the sexes. This in turn often necessitates differential modes of control of their activities in the two sexes.
In humans, mice and the fruit fly Drosophila melanogaster, for instance, female cells have two X chromosomes, males one X and one Y chromosome (the latter element is small and encodes very few genes). Mechanisms have evolved to ensure that the genes on the X make the same amounts of product in male and female cells. In Drosophila, this is achieved by boosting the activity of X-linked genes in males. In effect, active genes on the male X are expressed at twice the rate of their counterparts on each of the X chromosomes in female cells. This phenomenon is known as dosage compensation.
In Drosophila, mutations that disrupt dosage compensation are lethal to males. A protein-RNA complex called the Dosage Compensation Complex (DCC) plays a crucial role in matching levels of X-linked gene activity between the sexes. DCC only intervenes in the regulation of the genes on the X in males. “We wanted to know how its assembly and activity are regulated,” says LMU biologist Professor Peter Becker. “One important question is how DCC distinguishes the X chromosome from the non-sex chromosomes, the autosomes. Autosomal genes are not, and should not be, affected by DCC.”
Here too, the dosage turns out to be crucial. If male cells are forced to overproduce components of DCC, the surplus molecules bind to sites on the “wrong” chromosomes, the autosomes. The researchers therefore asked how this situation is avoided in normal cells. How do male cells ensure that the seven components of the DCC are produced in the appropriate amounts? Becker and his team were able to demonstrate that, in Drosophila, the DCC is equipped with an autoregulatory sensor and effector system that detects and corrects imbalances in the relative amounts of its various subunits.
Autoregulation – and more?
They discovered that one core element of the complex, the protein MSL2, possesses a previously unsuspected enzyme activity. MSL2 is an ubiquitin ligase, an enzyme that marks certain target proteins for degradation. Ubiquitin ligases work by attaching a short protein called ubiquitin to specific sites in proteins destined for demolition. MSL2 can attach these tags to itself, and to three of the other four proteins in the DCC. “We assume that incorrectly or incompletely assembled versions of the complex fail to pass internal quality controls and are destroyed,” says Becker.
However, the team also detected ubiquitinylated components of DCC in association with genes on the X chromosome. This suggests that not every ubiquitin-tagged protein is rapidly eliminated. “Based on this finding, we hypothesize that not all ubiquitin chains necessarily act as disposal tags,” says Becker. “It is conceivable that these molecules also serve as signals – although it is not yet clear what mechanisms they might act upon.”
(Molecular Cell online, 18 October 2012) suwe / PH