IISER Mohali, Knowledge city, Sector 81, SAS Nagar, Manauli PO 140306

Dr. Shravan Kumar Mishra
Associate Professor, Biological Sciences

Contact ABII-3F3 (Office) & ABII-4L2 (Lab)  
Email skmishra(AT)iisermohali.ac.in
Fax +91 172 2240266
ORCID ID https://orcid.org/0000-0003-3899-0495
Personal Page          

Mywebpage

                                                     
Research Area
Molecular Cell Biology

Research Topics
Ubiquitin-Like Modifiers and Control of Pre-mRNA Splicing

Research Focus

We study function and regulation of proteins related to ubiquitin in cellular processes of pre-messenger RNA splicing and signaling. For these studies, we perform experiments in molecular cell biology, genetics, and biochemistry in the budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe. We use mammalian cell cultures and multi-cellular organisms through collaborations to highlight relevance of our findings in humans.


Ubiquitin and ubiquitin-like modifiers, including Hub1, SUMO, NEDD8, Sde2, are a family of small proteins harboring ubiquitin fold. They function as central regulators for a large number of processes in the cell. The covalent attachment of ubiquitin to target proteins by the process known as ubiquitination requires a set of dedicated enzymes. Ubiquitination is the key for determining fate of target proteins through degradation in the proteasome. This process also diversifies functions of the targets by modulating their properties in non-proteolytic ways. Other ubiquitin-like modifiers also attach to their targets for regulatory activities, both covalently and non-covalently. Ubiquitin-like modifiers thereby act as molecular switches in processes such as DNA repair, signal transduction, protein sorting etc.


The ubiquitin-like proteins Hub1 and Sde2 promote efficient excision of a subset of introns. They bind to targets only non-covalently and function in pre-mRNA splicing in unique ways. Hub1-modified spliceosomes are able to recognize suboptimal introns and promote alternative splicing. Whereas Hub1 is conserved from budding yeast to humans, the ubiquitin-fold-harboring Sde2 protein is found only in intron-rich eukaryotes, from fission yeast to humans. After removal of its ubiquitin fold by specific deubiquitinating enzymes, Sde2 gets incorporated into the spliceosome for intron-specific splicing. Thus, both Hub1 and Sde2 appear to relax spliceosomes’ fidelity on a subset of pre-mRNAs.


The hallmarks of many diseases in humans, including cancer, are the defects in heterochromatin silencing and genome stability. Our findings reveal that the process of intron-specific pre-mRNA splicing induced by ubiquitin-like proteins is critical for heterochromatin silencing and genome stability.


Selected Publications

 

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