Abstract
Somatic mutations in the spliceosome gene ZRSR2 — located on the X chromosome — are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3΄ splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here, we characterize ZRSR2 as an essential component of the minor spliceosome (U12-dependent) assembly. shRNA mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns, and RNA-Sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns while splicing of the U2-type introns remain mostly unaffected. ZRSR2 deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS.
Highlights
Somatic mutations in the spliceosome gene ZRSR2—located on the X chromosome—are associated with myelodysplastic syndrome (MDS)
In MDS, somatic mutations in ZRSR2 occur across the entire length of the transcript, which is in contrast to mutational hotspots observed in SF3B1, SRSF2 and U2AF1
In a previous study, ectopic expression of mutant U2AF1—a splice factor related to ZRSR2 and frequently mutated in MDS—results in higher frequency of exon skipping from GH1 minigene construct[12]
Summary
Somatic mutations in the spliceosome gene ZRSR2—located on the X chromosome—are associated with myelodysplastic syndrome (MDS). ShRNA-mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns and RNA-sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns, while splicing of the U2-type introns remain mostly unaffected. ZRSR2-deficient cells exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS. This study uncovers a specific function of ZRSR2 in RNA splicing and suggests its role in haematopoietic development
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