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Title: ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
Authors: Madan, Vikas
Cao, Zeya
Teoh, Weoi Woon
Dakle, Pushkar
Han, Lin
Shyamsunder, Pavithra
Jeitany, Maya
Zhou, Siqin
Li, Jia
Hazimah Mohd Nordin
Shi, JiZhong
Yu, Shuizhou
Yang, Henry
Md Zakir Hossain
Chng, Wee Joo
Koeffler, H Phillip
Keywords: Science::Medicine
Issue Date: 2022
Source: Madan, V., Cao, Z., Teoh, W. W., Dakle, P., Han, L., Shyamsunder, P., Jeitany, M., Zhou, S., Li, J., Hazimah Mohd Nordin, Shi, J., Yu, S., Yang, H., Md Zakir Hossain, Chng, W. J. & Koeffler, H. P. (2022). ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells. Haematologica, 107(3), 680-689.
Project: NMRC/CG/012/2013
Journal: Haematologica
Abstract: Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. In order to further investigate the role of this splice factor in RNA splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in both competitive and non-competitive reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2-deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not in human cells contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to accurately model ZRSR2-mutant MDS in mice.
ISSN: 0390-6078
DOI: 10.3324/haematol.2020.260562
Schools: School of Biological Sciences 
Organisations: Cancer Science Institute of Singapore, NUS
Rights: © 2022 Ferrata Storti Foundation. Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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