The role of <scp>SON</scp> in splicing, development, and disease

Lu, Xinyi; Ng, Huck Hui; Bubulya, Paula A.

doi:10.1002/wrna.1235

Cited by 36 publications

(35 citation statements)

References 58 publications

(241 reference statements)

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“…SON was shown to be a scaffold/structural nuclear speckle factor and its depletion leads to dispersion of splicing factors from nuclear speckles to the nucleoplasm 28, 29 . SON was also shown to regulate cell cycle progression, development, and disease 28, 29 . In control cells where SON is not depleted, we found that most of the M mRNA is in the cytoplasm at 6h post-infection (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We then investigated whether NS1 and the cellular proteins involved in M1 mRNA localization and splicing at nuclear speckles physically interact with SON, a major player in nuclear speckle assembly and alternative splicing 28, 29 . The major form of the SON protein is ~263 kD and runs as a broad band in SDS- PAGE as it is likely post-translationally modified.…”

Section: Resultsmentioning

confidence: 99%

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Influenza virus mRNA trafficking through host nuclear speckles

et al. 2016

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Influenza A virus is a human pathogen whose genome is comprised of eight viral RNA segments that replicate in the nucleus. Two viral mRNAs are alternatively spliced. The unspliced M1 mRNA is translated into the matrix M1 protein while the ion channel M2 protein is generated after alternative splicing. These proteins are critical mediators of viral trafficking and budding. We show that influenza virus utilizes nuclear speckles to promote post-transcriptional splicing of its M1 mRNA. We assign previously unknown roles for the viral NS1 protein and cellular factors to an intranuclear trafficking pathway that targets the viral M1 mRNA to nuclear speckles, mediates splicing at these nuclear bodies, and exports the spliced M2 mRNA from the nucleus. Since nuclear speckles are storage sites for splicing factors, which leave these sites to splice cellular pre-mRNAs at transcribing genes, we reveal a functional subversion of nuclear speckles to promote viral gene expression.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Influenza virus mRNA trafficking through host nuclear speckles

et al. 2016

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“…SON is a ubiquitously expressed and evolutionarily conserved gene in vertebrates and is located on the human chromosome region 21q22.11 [4]. It encodes the DNA-and RNA-binding protein SON, which functions in RNA splicing as well as gene repression [7][8][9][10][11][12][13]. A wide variety of genes are, thus, under the control of SON, and SON has been reported to be involved in cell cycle regulation and stem cell maintenance [7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities.

Matsuki¹,

Fukada²,

Eda³

et al. 2020

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Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, a rare congenital anomaly syndrome characterized by intellectual disability, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and some visceral malformations is caused by de novo heterozygous mutations of the SON gene. The nuclear protein SON is involved in gene transcription and RNA splicing; however, the roles of SON in neural development remain undetermined. We investigated the effects of Son knockdown on neural development in mice and found that Son knockdown in neural progenitors resulted in defective migration during corticogenesis and reduced spine density on mature cortical neurons. The induction of human wild-type SON expression rescued these neural abnormalities, confirming that the abnormalities were caused by SON insufficiency. We also applied truncated SON proteins encoded by disease-associated mutant SON genes for rescue experiments and found that a truncated SON protein encoded by the most prevalent SON mutant found in ZTTK syndrome rescued the neural abnormalities while another much shorter mutant SON protein did not. These data indicate that SON insufficiency causes neuronal migration defects and dendritic spine abnormalities, which seem neuropathological bases of the neural symptoms of ZTTK syndrome. In addition, the results support that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.

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“…SON is required for proper RNA splicing of selective genes (Ahn et al, 2011; Hickey et al, 2014; Lu et al, 2013; Lu et al, 2014; Martello, 2013; Sharma et al, 2011). Knockdown of SON leads to splicing defects in transcripts containing weak splice sites, and many of the affected genes are necessary for cell cycle progression and epigenetic modification (Ahn et al, 2011; Sharma et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes

et al. 2016

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SUMMARY Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy, but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.

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The role of SON in splicing, development, and disease

Cited by 36 publications

References 58 publications

Influenza virus mRNA trafficking through host nuclear speckles

Influenza virus mRNA trafficking through host nuclear speckles

Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities.

SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes

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