Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome

Vikas Madan (), Deepika Kanojia, Jia Li, Ryoko Okamoto, Aiko Sato-Otsubo, Alexander Kohlmann, Masashi Sanada, Vera Grossmann, Janani Sundaresan, Yuichi Shiraishi, Satoru Miyano, Felicitas Thol, Arnold Ganser, Henry Yang (), Torsten Haferlach, Seishi Ogawa and H. Phillip Koeffler
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Vikas Madan: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Singapore 117599, Singapore
Deepika Kanojia: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Singapore 117599, Singapore
Jia Li: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Singapore 117599, Singapore
Ryoko Okamoto: Cedars-Sinai Medical Center, UCLA School of Medicine
Aiko Sato-Otsubo: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo
Alexander Kohlmann: MLL Munich Leukemia Laboratory
Masashi Sanada: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo
Vera Grossmann: MLL Munich Leukemia Laboratory
Janani Sundaresan: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Singapore 117599, Singapore
Yuichi Shiraishi: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo
Satoru Miyano: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo
Felicitas Thol: Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School
Arnold Ganser: Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School
Henry Yang: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Singapore 117599, Singapore
Torsten Haferlach: MLL Munich Leukemia Laboratory
Seishi Ogawa: Cancer Genomics Project, Graduate School of Medicine, University of Tokyo
H. Phillip Koeffler: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Singapore 117599, Singapore

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7042

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