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dc.contributor.authorMadan, Vikasen_US
dc.contributor.authorCao, Zeyaen_US
dc.contributor.authorTeoh, Weoi Woonen_US
dc.contributor.authorDakle, Pushkaren_US
dc.contributor.authorHan, Linen_US
dc.contributor.authorShyamsunder, Pavithraen_US
dc.contributor.authorJeitany, Mayaen_US
dc.contributor.authorZhou, Siqinen_US
dc.contributor.authorLi, Jiaen_US
dc.contributor.authorHazimah Mohd Nordinen_US
dc.contributor.authorShi, JiZhongen_US
dc.contributor.authorYu, Shuizhouen_US
dc.contributor.authorYang, Henryen_US
dc.contributor.authorMd Zakir Hossainen_US
dc.contributor.authorChng, Wee Jooen_US
dc.contributor.authorKoeffler, H Phillipen_US
dc.identifier.citationMadan, 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.
dc.description.abstractRecurrent 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.en_US
dc.description.sponsorshipMinistry of Education (MOE)en_US
dc.description.sponsorshipMinistry of Health (MOH)en_US
dc.description.sponsorshipNational Medical Research Council (NMRC)en_US
dc.description.sponsorshipNational Research Foundation (NRF)en_US
dc.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.en_US
dc.titleZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cellsen_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.contributor.organizationCancer Science Institute of Singapore, NUSen_US
dc.description.versionPublished versionen_US
dc.subject.keywordsProtein P53en_US
dc.subject.keywordsHematopoietic Cellen_US
dc.description.acknowledgementThis work was funded by the Leukemia and Lymphoma Society, the Singapore Ministry of Health’s National Medical Research Council (NMRC) under its Singapore Translational Research (STaR) Investigator Award to HPK (NMRC/STaR/0021/2014), the NMRC Center Grant awarded to the National University Cancer Institute of Singapore (NMRC/CG/012/2013) and the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiatives. This research is also supported by the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s Tier 3 grants, grant number MOE2014-T3-1-006. We thank the Melamed Family for their generous support.en_US
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