Post-Doctoral: Pre-mRNA Splicing, University of California, Los Angeles
PhD: Indian Institute of Science, Bangalore, India
Pre-mRNA splicing is an essential step in expression of protein coding genes. Splicing removes non-coding introns and very precisely joins coding exons to form mature mRNA that can be translated into functional proteins. The splicing process is catalyzed by a very dynamic mutli-megadalton RNP complex called the Spliceosome. Interestingly, somatic mutations in many proteins of the splicing machinery occur at a high frequency in many myeloid malignancies including myelodysplastic syndromes (~50-60%), chronic myelomonocytic leukemia (~50%), and acute myeloid leukemia (~15%).
Research in the Sharma lab focuses on understanding mechanisms by which RNA and proteins components of the spliceosome select splice sites in pre-mRNAs, and how occurrence of splicing factor mutations in hematopoietic stem and progenitor cells leads to a myeloid disease phenotype. Our studies have recently identified a new type of RNA binding motif, a Ubiquitin-like domain, in splicing factor 3A1, and shown that MDS mutations in this domain impact RNA binding. We have also shown that mutations of another myeloid disease protein, the serine-arginine rich splicing factor 2, can cause abnormal differentiation of human hematopoietic stem and progenitor cells.
- Martelly W, Fellows B, Senior K, Marlowe T, and Sharma S (2019) Identification of a non-canonical RNA binding domain in the U2 snRNP protein SF3A1, RNA 25, 1509-21. PMCID: PMC6795144
- Bapat A, Keita N, and Sharma S (2019) Pan-myeloid differentiation of human cord blood derived CD34+ hematopoietic stem and progenitor cells, J. Vis. Exp. 150, e59836. PMCID: PMC7046082
- Bapat A, Keita N, Martelly W, Kang P, Seet C, Stoilov P, Jacobsen, JR, Hu C, Crooks GM, and Sharma S (2018) Myeloid disease mutations of splicing factor SRSF2 cause G2-M arrest and skewed differentiation of human hematopoietic stem and progenitor cells, Stem Cells 36:1663-1675. PMCID: PMC6283046
- Wongpalee S, Vashist A, Sharma S, Wohlschlegel J, and Black DL (2016) Large-scale remodeling of a repressed exon ribonucleoprotein to an exon definition complex active for splicing, eLife 5:e19743. PMCID: PMC5122456
- Sharma S*, Wongpalee S, Vashist A, Wohlschlegel J, and Black DL (2014) Stem-loop 4 of U1 snRNA is essential for splicing and interacts with the U2 snRNP specific SF3A1 protein during spliceosome assembly, Genes and Development 28, 2518-31. PMCID: PMC4233244 (*First and Co-corresponding author)
For a complete listing of Dr. Sharma's publications, click here.