Rajyaguru Lab
Department of Biochemistry
Indian Institute of Science
Research
Our broad research interests focus on posttranscriptional gene control mechanisms in health and disease. We are intrigued by 'how does a cell decide to translate, store or degrade an mRNA at a given time?'. This question is relevant because mRNA fate decisions at the level of translation/decay play a critical role in various cellular processes as well as in diseases. Apart from addressing the mechanics of this fundamental problem, in our lab, we also focus on contribution of mRNA fate decisions to neurodegenerative disorders (like Amyotrophic Lateral Sclerosis - ALS) and Cancer. We are specifically interested in understanding the mechanisms underlying mRNA fate decisions governed by RNA-protein complexes referred to as ‘RNA granules’ or ‘RNP condensates’. We apply a combination of biochemical, genetic, live-cell imaging and genomic approaches to address our research questions using yeast (S. cerevisiae) and mammalian cell culture system for addressing these questions.
We are excited to address the following questions
1. How do low complexity sequences in proteins affect mRNA fate?
Low complexity sequences are characterized by repeats of amino acids of variable length. Some examples of such sequences are repeats of QN, RGG, SR, proline, glutamine, etc. We are interested in focussing on the role of RGG-repeat containing sequences in RNA-binding proteins. These proteins play a key role in several RNA metabolic processes. We focus on the role of these proteins in movement of mRNAs in and out of translation and decay steps. Interestingly, RGG-repeats (motifs) are sites of arginine methylation as well. We also focus on the role of arginine methylation in regulating RGG-repeat mediated mRNA fate decisions.
2. How do RNA granules (RNP condensates) disassemble?
RNA granules are conserved membrane-less RNA-protein complexes. The granules are also referred to as mRNP condensates and play a critical role in determining the functional status of mRNA in the cell. P-bodies and stress granules are well-characterized forms of RNA granules. The assembly mechanisms of RNA granules are well characterized. However we are focussing on disassembly of these granules which remains poorly understood.
3. How do altered RNP condensate dynamics contribute to disease?
A strong motivation for understanding disassembly mechanisms is provided by observations highlighting the contribution of RNP condensates in several neurodegenerative disorders such as ALS/FTLD and certain Cancer (melanoma and lung cancer). ALS patients are characterized by the accumulation of disassembly defective protein aggregates that often contain key RNA-binding proteins and colocalize with physiological RNP condensates. Several anti-cancer therapies induce RNP condensate assembly that reduces the drug effectiveness leading to cancer relapse. Condensate disassembly as an effective therapeutic intervention is an emerging idea which our group is currently actively exploring.
4. Why and how do RNA processes in the nucleus and the cytoplasm crosstalk?
Mature mRNAs are exported from the nucleus to the cytoplasm in complex with predominantly nuclear shuttling RNA-binding proteins. We hypothesize a role of these shuttling proteins in regulating mRNA fate in the cytoplasm. Such a role is likely to act as a conduit for their role in nucleus to co-ordinate different steps of gene expression spanning from nucleus to the cytoplasm. On the other hand we are also excited to address possible nuclear role of predominantly cytoplasmic RNA-binding proteins. We hypothesize these proteins to travel to the nucleus in response to physiological cues such as genotoxic stress to modulate gene expression. The details underlying such cross-talk mechanisms fascinate us.
