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Abstract ID 95171 Poster Board 450 Polypyrimidine tract binding protein 1 (PTBP1) is one of the most well-described RNA binding proteins, known initially for its role as a splicing repressor before later studies revealed its numerous roles in regulation of RNA maturation and utilization. Understanding how loss of a single RNA binding domain (RBD) in multi-domain proteins is essential for development of small molecule RBD inhibitors. There are several types of RBD's (e.g., KH domain, zinc-finger domain), but the RNA recognition motif (RRM) is the most abundant and well characterized both structurally and biochemically. PTBP1 is a multi-RBD protein that contains four RRM's and prior structural characterization has demonstrated these domains are heterogenous in both structure and RNA binding preferences, yet no studies have determined the relative contribution of each RRM to overall PTBP1 function. Here we show that deletion of RRM1 impacts overall expression of genes involved in nervous system development, immune regulation, and cell-cell adhesion, as well as exon utilization in the WNT signaling pathway. Further, these transcriptomic changes observed upon deletion of RRM1 also translated phenotypically to enhanced migration compared to wild-type full length protein without enhancing proliferation. Overall, our findings confirm that RRM1 has a discreate role in the overall function of PTBP1 both in mRNA splicing and exon utilization. This novel mechanism of RRM1 regulation highlights the importance of understanding the functional dynamics with which RRM1 contributes to PTBP1 function, and how further investigations of small molecule inhibition targeting RRM1 could lead to decreased migration and tumor invasion in glioblastoma.
Acton et al. (Mon,) studied this question.