期刊
NATURE GENETICS
卷 53, 期 5, 页码 707-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-021-00828-9
关键词
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资金
- Conquer Cancer Foundation of the American Society of Clinical Oncology
- American Association for Cancer Research
- American Society of Hematology
- Robert Wood Johnson Foundation
- ARCS Foundation
- NIH [1K08CA23031901, T32 CA009657, R01 DK103854, R01 HL151651, R01 HL128239, R01 CA251138]
- Department of Defense Bone Marrow Failure Research Program [W81XWH-12-1-0041]
- Leukemia & Lymphoma Society
- Henry and Marilyn Taub Foundation
- Edward P. Evans MDS Foundation
- Blood Cancer Discoveries Grant program through the Leukemia & Lymphoma Society
- Mark Foundation for Cancer Research
- Paul G. Allen Frontiers Group [8023-20]
- AMED [JP19cm0106165, JP20cm0106165]
- Takeda Science Foundation
- MDS Foundation
- Yasuda Medical Foundation
- Kanae Foundation for the Promotion of Medical Science
- MSD Life Science Foundation
- Bristol Myers Squibb Foundation
- JSPS KAKENHI [JP20H00537, JP 20H03717]
- Leukemia Research Foundation
Loss of function of the minor spliceosome component ZRSR2 enhances hematopoietic stem cell self-renewal through minor intron retention of its target LZTR1, a regulator of RAS-related GTPases. Retention of LZTR1 minor introns was also identified in Noonan syndrome and different solid tumors, suggesting a potential link between minor intron recognition and regulation of hematopoiesis and cancers. Recurrent mutations in ZRSR2, minor introns, and LZTR1 suggest potential connections among ZRSR2 mutations, LZTR1 regulation, and leukemia development.
Loss of function of the minor spliceosome component ZRSR2 enhances hematopoietic stem cell self-renewal through minor intron retention of its target LZTR1, which is a regulator of RAS-related GTPases. Minor intron retention of LZTR1 was also identified in Noonan syndrome and diverse solid tumor types. Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.
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