Transcriptional Coactivator and Oncoprotein CoAA

Abstract

CoAA contains two copies of RNA recognition motifs (RRM) and an intrinsic transactivation domain rich in repetitive tyrosines and glutamines (YxxQ domain). Previously, CoAA has been shown to be a transcriptional coactivator that stimulates transcriptional activation and regulates alternative splicing. A pattern and profile search revealed that the YxxQ domain in CoAA shared significant pattern homology with the oncogenic EWS activation domains (EAD) in TET family proteins, including, TLS/FUS, EWS and TAFII 68. It was further demonstrated that CoAA’s YxxQ domain and EWS’ EAD also shared functional similarities. Based on these findings, this work investigated the aberration of CoAA in cancers and its pathophysiological significance. The results showed that the CoAA gene was amplified in a high percentage of inflammation-related human cancers with recurrent loss of the 5’ regulatory element upstream of its promoter. This genomic aberration resulted in CoAA protein overexpression, which in turn, induced the transformation of NIH3T3 cells. Subsequently, it was shown that the lost 5’ regulatory element could modulate the alternative splicing of the CoAA gene during stem cell differentiation and that the unbalanced expression of CoAA and its splice variant, CoAM could potentially impact the cell differentiation process. To further characterize the regulation of CoAA alternative splicing, two conserved trans-splicing events between CoAA and its downstream RBM4 were identified. These events yield a novel zinc finger- containing coactivator, CoAZ, and a non-coding splice variant, ncCoAZ. Both variants regulated their parental genes’ mRNA expression as well as activities, suggesting a linked control between CoAA and RBM4. Moreover, the expression patterns of CoAA, RBM4 and their trans-splicing variants switched during neural stem cell differentiation, resulting in lineage-specific expression of each variant. Our phylogenetic analysis suggests that mammalian CoAA and RBM4 share a common ancestor with the Drosophila melanogaster gene, Lark. In this regard, the trans-splicing events between CoAA and RBM4 represent a functional regulation preserved during evolution. This study established the connection between CoAA and human cancer and provides evidence for CoAA’s involvement in the regulation of cell differentiation. Moreover, this study is the first to report a functional trans-splicing variant in mammalian cells.