Shalini Sharma, PhD

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.