A molecular model of DNA containing two modified base J residues. The additional glucose moiety (in red) sticks out into the major groove of the DNA helix. On the left is a model of unmodified DNA. Courtesy of Robert Sabatini, Marine Biological laboratory, Woods Hole, USA.

A newly identified trypanosome protein that regulates synthesis of a modified thymine base in their DNA could be a crucial element in the parasite's ability to avoid detection by the immune system of their hosts.

Trypanosomes evade the human immune response by periodically switching the make-up of the variant surface glycoprotein (VSG) that is present on the surface of the parasitic cell through a process called antigenic variation. The trypanosome has approximately 1,000 different VSG genes, but only expresses one at a time, while the others are somehow silenced. The molecular basis for this gene-silencing process is not known, but one hypothesis suggests that the modified DNA base J (β-D-glucosylhydroxymethyluracil) is involved, because of the presence of the base within inactive, telomeric, VSG gene-expression sites and its absence from the active expression site.

To explore the process of antigenic variation and the possible role of J, Robert Sabatini and colleagues set out to understand the molecular basis of J biosynthesis and regulation. Previously, the authors had identified a J-binding protein (JBP1) that was involved in propagating J synthesis along the chromosome. Reporting in a recent issue of Molecular Cell, DiPaolo et al. have now discovered a second regulatory protein involved in J biosynthesis. JBP2 is a homologue of JBP1 and contains a domain that is related to the SWI2/SNF2 family of chromatin remodelling proteins.

Initially, the authors demonstrated that JBP2 expression is upregulated in the bloodstream form of the parasite, the part of the trypanosome life cycle in which its DNA is modified. It was also shown that JBP2 associates with nuclear chromatin and that expression of the protein stimulates de novo synthesis of a basal level of J along the chromosome. Mutation of crucial residues within the SWI2/SNF2 domain abrogated this activity, leading the authors to propose that JBP2 catalyses the remodelling of nuclear chromatin and allows access of the J-synthesis machinery to a thymine base. DiPaolo et al. were also able to show that, once the modified base J is introduced into the chromosome, it is maintained and propagated by JBP1, independent of the chromatin context. As the expression of JBP2 is developmentally regulated, the authors propose that this protein is the crucial cofactor that controls the synthesis of J and its specific localization in the bloodstream form of the trypanosome genome.

Further work will be required to elucidate the precise role of J in trypanosome biology and whether the modified base is crucial to the process of antigenic variation. In that event, creating a drug that inactivates JBP2 has the potential to inhibit the ability of the parasite to evade the human immune system and form the basis of a much-needed effective therapy against trypanosome infection.