Alternative Splicing Mediates the Compensatory Upregulation of MBNL2 Upon MBNL1 Loss-of-Function

Authors

Larissa Nitschke
Rong-Chi Hu
Andrew N Miller
Lathan Lucas
Thomas A Cooper

Publication Date

2-22-2023

Journal

Nucleic Acids Research

DOI

10.1093/nar/gkac1219

PMID

36617982

PMCID

PMC9943662

PubMedCentral® Posted Date

1-9-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Alternative Splicing, DNA-Binding Proteins, Exons, Myotonic Dystrophy, RNA-Binding Proteins, Transcriptional Activation, Up-Regulation

Abstract

Loss of gene function can be compensated by paralogs with redundant functions. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while the inclusion of Mbnl2 exon 9 shifts the reading frame to an alternative C-terminus. We show that the C-terminus lacking exon 9 contains a PEST domain which causes proteasomal degradation. Loss of MBNL1 increases the inclusion of exon 9, resulting in an alternative C-terminus lacking the PEST domain and the increase of MBNL2. We further find that the compensatory mechanism is active in a mouse DM1 model. Together, this study uncovers the compensatory mechanism by which loss of MBNL1 upregulates its paralog MBNL2 and highlights a potential role of the compensatory mechanism in DM1.