On March 22^nd, 2023, Nature Communications published a paper from the Li lab: ???The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression??? by Gaurav et al.

Dr. Bibo Li is a professor in the Center for Gene Regulation in Health and Disease and the Department of Biological, Geological, Environmental Sciences. The Li lab has been studying telomere functions in antigenic variation in Trypanosoma brucei that causes debilitating sleeping sickness in humans. T. brucei sequentially expresses distinct Variant Surface Glycoproteins (VSGs) as its major surface antigen to evade the host???s immune response. At any moment, only a single type of VSG is presented on the parasite surface even though the T. brucei genome has numerous different VSG genes. Parasites expressing multiple different VSGs are eliminated by its mammalian host more efficiently, indicating that VSG monoallelic expression is essential for parasite survival. VSGs are expressed exclusive from regions adjacent to telomeres ??? nucleoprotein complexes at chromosome ends that are essential for genome integrity. The Li lab was the first one demonstrated that proteins associated with the telomere play essential functions in antigenic variation in T. brucei. Specifically, the Li lab has demonstrated that TbRAP1, a telomere protein, is a key player regulating VSG monoallelic expression and has published several high profile papers on TbRAP1???s function throughout the years (Yang et al. 2009. Cell 137: 99, as a cover story; Pandya et al. 2013. NAR 41:7673; Nanavaty et al. 2017. NAR. 45:5785; Afrin et al. 2020. Science Advances. 6: eabc4065)

The current Nature Communications paper from the Li lab has several striking findings. First, Gaurav et al. identified unexpected that TbRAP1 has an RNA Recognition Motif (RRM) and that TbRAP1 binds the active VSG RNA through its RRM domain. This is a novel finding as none of known RAP1 homologs have been reported to have any RRM domains or RNA binding activities. Second, this newly discovered RNA binding activity competes with TbRAP1???s dsDNA binding activity that was also identified by the Li lab recently (Afrin et al. 2020. Science Advances. 6: eabc4065). Such competition between the same protein???s DNA and RNA binding activities is rare. Third, the competition between TbRAP1???s RNA and DNA binding activities is essential for full-level expression of the active VSG, revealing a previously unknown mechanism of VSG monoallelic expression, leading to an uncharted area of research and facilitating a deeper understanding of antigenic variation in T. brucei. Notably, the RAP1 RRM domain is highly conserved among Trypanosomatids but absent in higher eukaryotes. With this unique feature and activity likely conserved in Trypanosomatida organisms, TbRAP1 can serve as a promising target for antiparasitic agents.

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