Publication in Science Advances by JIN Yongfeng's Laboratory, Institute of Biochemistry

Title: Hidden RNA pairings counteract the “first-come, first-served” splicing principle to drive stochastic choice in Dscam1 splice variants

HAIYANG DONG, BINGBING XU, PENGJUAN GUO, JIAN ZHANG, XI YANG, LEI LI, YING FU, JILONG SHI, SHIXIN ZHANG, YANDA ZHU, YANG SHI, FENGYAN ZHOU, LINA BIAN, WENDONG YOU, FENG SHI, XIAOFENG YANG, JIANHUA HUANG, HAIHUAI HE, AND YONGFENG JIN

SCIENCE ADVANCES • 26 Jan 2022 • Vol 8, Issue 4 •

DOI: 10.1126/sciadv.abm1763

Abstract

Drosophila melanogaster Dscam1 encodes 38,016 isoforms via mutually exclusive splicing; however, the regulatory mechanism behind this is not fully understood. Here, we found a set of hidden RNA secondary structures that balance the stochastic choice of Dscam1 splice variants (designated balancer RNA secondary structures). In vivo mutational analyses revealed the dual function of these balancer interactions in driving the stochastic choice of splice variants, through enhancement of the inclusion of distal exon 6s by cooperating with docking site–selector pairing to form a stronger multidomain pre-mRNA structure and through simultaneous repression of the inclusion of proximal exon 6s by antagonizing their docking site–selector pairings. Thus, we provide an elegant molecular model based on competition and cooperation between two sets of docking site–selector and balancer pairings, which counteracts the “first-come, first-served” principle. Our findings provide conceptual and mechanistic insight into the dynamics and functions of long-range RNA secondary structures.

Link:  https://www.science.org/doi/10.1126/sciadv.abm1763

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