Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition

Autor: Benjamin H. Durham, Yasutaka Hayashi, Frank McCormick, Sanjoy Mehta, Atsushi Tanaka, Hiromi Yamazaki, Ettaib El Marabti, Chie Fukui, Ralph Garippa, Bo Liu, Guo-Liang Chew, Sydney X. Lu, Jacob T. Polaski, Alex Penson, Justin Taylor, Eric Wang, Sisi Chen, Daichi Inoue, Simon J. Hogg, Daniel Zakheim, Caroline Erickson, Jose Mario Bello Pineda, Miki Fukumoto, Pau Castel, Omar Abdel-Wahab, Susumu Kobayashi, Katherine Knorr, Robert K. Bradley
Rok vydání: 2021
Předmět:
Male
GTPase
Cell Transformation
Medical and Health Sciences
Mice
0302 clinical medicine
Minor spliceosome
Neoplasms
2.1 Biological and endogenous factors
Cell Self Renewal
Aetiology
Cancer
Mice
Knockout
Genetics
0303 health sciences
Genome
Noonan Syndrome
Hematology
Biological Sciences
Pedigree
Cell Transformation
Neoplastic
Ribonucleoproteins
RNA splicing
Female
Human
Spliceosome
Knockout
RNA Splicing
Biology
RASopathy
Article
03 medical and health sciences
Rare Diseases
Cancer stem cell
medicine
Animals
Humans
Genetic Predisposition to Disease
Loss function
030304 developmental biology
Neoplastic
Base Sequence
Genome
Human
Intron
Hematopoietic Stem Cells
Stem Cell Research
medicine.disease
Hematologic Diseases
Introns
Clone Cells
RNA
CRISPR-Cas Systems
Spleen
030217 neurology & neurosurgery
Transcription Factors
Developmental Biology
Zdroj: Nature genetics, vol 53, iss 5
Nature genetics
ISSN: 1546-1718
1061-4036
DOI: 10.1038/s41588-021-00828-9
Popis: 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. 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.
Databáze: OpenAIRE
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