We are interested in molecular mechanisms that allow mammalian cells to maintain homeostasis, respond to pathogens and damage, or become metastatic cancers when these mechanisms lose balance. We employ structural, cell, computational and chemical biology, as well as emerging methods of high-throughput systems biology. We focus on pathways mediated by receptors of dsRNA and on signaling proteins from the kinase family, which mediate post-transcriptional gene regulation.
Receptors of dsRNA
Mammalian cells accumulate double-stranded RNA or dsRNA not only from viral infections, but also from still mysterious endogenous sources. For example, from cancer-triggered transcription of centromeric repeats, ubiquitous Alu elements, which expanded massively within coding and non-coding RNA in primates, or antisense transcription. Multiple transmembrane and intracellular proteins encoded in mammalian genomes serve as receptors that recognize dsRNA to maintain homeostasis and mount stress and immune responses. We are especially interested in the family of dsRNA receptors that use second messengers for post-transcriptional gene regulation.
Post-transcriptional gene control
One of the ubiquitous pathways activated by dsRNA in all mammalian tissues involves regulated decay of the intracellular RNA pool by the kinase homology receptor, RNase L. Our work is focused on structural, cell, and chemical biology of RNase L. Moreover, we are interested in a sister protein of RNase L, Ire1. Ire1 activates the unfolded protein response (UPR) via a non-spliceosomal splicing of a non-canonical cytoplasmic intron present in mRNA of transcription factor XBP1. Physiologically, XBP1 promotes B-cell differentiation into antibody-producing plasma cells. In disease, XBP1 splicing can drive Multiple Myeloma, as well as take place specifically in aggressive breast cancers. We have shown recently that Ire1 and RNase L use similar mechanisms of activation and similar sequence rules for regulated RNA decay,
Human/murine cell biology
Our work is funded by Princeton University, Sidney Kimmel Foundation, Burroughs Wellcome Foundation, and NIH.