Characterization of human placental glycosaminoglycans and regional binding to VAR2CSA in malaria infected erythrocytes.

Placental malaria is a serious problem in sub-Saharan Africa. Young women are particular susceptible to contracting this form of malaria during their first or second pregnancy despite previously acquired immunity from past infections. Placental malaria is caused by Plasmodium falciparum parasites expressing VAR2CSA on the erythrocyte surface.

Glycosaminoglycans in infectious disease.

Glycosaminoglycans (GAGs) are complex carbohydrates that are ubiquitously present on the cell surface and in the extracellular matrix. Interactions between GAGs and pathogens represent the first line of contact between pathogen and host cell and are crucial to a pathogen's invasive potential. Their complexity and structural diversity allow GAGs to control a wide array of biological interactions influencing many physiological and pathological processes, including adhesion, cell-to-cell communication, biochemical cascades, and the immune response.

Genome-wide activation of latent donor splice sites in stress and disease.

Sequences that conform to the 5' splice site (5'SS) consensus are highly abundant in mammalian introns. Most of these sequences are preceded by at least one in-frame stop codon; thus, their use for splicing would result in pre-maturely terminated aberrant mRNAs. In normally grown cells, such intronic 5'SSs appear not to be selected for splicing.

A potential role for initiator-tRNA in pre-mRNA splicing regulation.

The translation initiator-tRNA plays a crucial role in the initiation of protein synthesis in both prokaryotic and eukaryotic cells, by employing specific base pairing between its anticodon triplet CAU and the general initiation codon AUG in the mRNA. Here we show that the initiator-tRNA may also act, in a manner that is independent of its role in protein translation, as a pre-mRNA splicing regulator. Specifically, we show that alternative splicing events that are induced by mutations in the translation initiation AUG codon can be suppressed by expressing initiator-tRNA constructs carrying anticodon mutations that compensate for the AUG mutations.

AUG sequences are required to sustain nonsense-codon-mediated suppression of splicing.

More than 90% of human genes are rich in intronic latent 5' splice sites whose utilization in pre-mRNA splicing would introduce in-frame stop codons into the resultant mRNAs. We have therefore hypothesized that suppression of splicing (SOS) at latent 5' splice sites regulates alternative 5' splice site selection in a way that prevents the production of toxic nonsense mRNAs and verified this idea by showing that the removal of such in-frame stop codons is sufficient to activate latent splicing. Splicing control by SOS requires recognition of the mRNA reading frame, presumably recognizing the start codon sequence.