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VRK1 phosphorylates SRRM2 for the regulation of splicing of DNA damage repair factors

ABSTRACT: Vaccinia-related kinase 1 (VRK1) is a nuclear serine/threonine kinase that contributes to genome stability through the phosphorylation of diverse substrates. This study investigated whether VRK1 regulates pre-messenger RNA splicing through serine/arginine repetitive matrix protein 2 (SRRM2), a nuclear speckle-associated splicing scaffold. Messenger RNA sequencing was performed in control HEK293T cells, VRK1-knockout HEK293T cells, and SRRM2-depleted HEK293T cells. Alternative splicing events were analyzed using replicate Multivariate Analysis of Transcript Splicing. Most differential alternative splicing events detected following VRK1 knockout or SRRM2 depletion were skipped-exon events. A subset of skipped-exon events was shared between VRK1-knockout and SRRM2-depleted cells, and the corresponding genes were enriched in DNA repair-related pathways. These data support a role for the VRK1-SRRM2 regulatory axis in maintaining the efficient alternative splicing of DNA damage response-related transcripts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338004 | GEO | 2026/07/22

REPOSITORIES: GEO

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VRK1 phosphorylates SRRM2 for the regulation of splicing of DNA damage repair factors

Project description:Vaccinia-related kinase 1 (VRK1) is a nuclear serine/threonine kinase that contributes to genome stability through the phosphorylation of diverse substrates. This study investigated whether VRK1 regulates pre-messenger RNA splicing through serine/arginine repetitive matrix protein 2 (SRRM2), a nuclear speckle-associated splicing scaffold. Messenger RNA sequencing was performed in control HEK293T cells, VRK1-knockout HEK293T cells, and SRRM2-depleted HEK293T cells. Alternative splicing events were analyzed using replicate Multivariate Analysis of Transcript Splicing. Most differential alternative splicing events detected following VRK1 knockout or SRRM2 depletion were skipped-exon events. A subset of skipped-exon events was shared between VRK1-knockout and SRRM2-depleted cells, and the corresponding genes were enriched in DNA repair-related pathways. These data support a role for the VRK1-SRRM2 regulatory axis in maintaining the efficient alternative splicing of DNA damage response-related transcripts.

2026-07-09 | PXD080922 |

Alternative splicing analysis of SRRM1 or SRRM2 targets in THP-1 cells

Project description:We reported the joint SRRM1/2 regulation is not the major mechanism of SRRM2-mediated alternative splicing, and that maintenance of splicing condensates by SRRM2 is important for proper alternative splicing. We knocked SRRM1/2 down with three different shRNAs, performed RNA-seq and derived the differential alternative splicing events (DASEs) using rMATS. DASEs of SRRM1/2 were largely different with little overlap, and displayed a different splicing pattern. SRRM2 deficiency induces skipping of cassette exons with short introns and weak 5’ splice. Nearly 25% of the skipped events upon SRRM2 knockdown were unannotated. More than 40% of validated DASEs upon SRRM2 suppression were associated with protein domain change (>50% domain removed by splicing). Domain changes, and especially large region removal by multiple exon skipping is a significant mechanism for protein dysfunction. Thus, alternative splicing is the major mechanism for the maintenance of protein function and cell homeostasis by SRRM2.

2022-08-30 | GSE199720 | GEO

Hsa-miR-139-5p/HNRNPF axis modulates gene-transcripts balance in thyroid cancer cells

Project description:We explored alternative splicing events upon hsa-miR-139-5p/HNRNPF axis regulation in our cell system using the Multivariate Analysis of Transcript Splicing (rMATS) computational tool (https://doi.org/10.1073/pnas.1419161111). Differential analysis of major splicing outcomes (skipped exon, alternative 5’/3’ splice, mutually exclusive exons and retained intron) revealed a total of 174 events significantly activated or repressed (FDR<0.05) upon HNRNPF regulation.

2019-08-26 | GSE123680 | GEO

Transcriptome of ΔPfPRMT5 parasite during malaria parasite asexual development [PRMT5_RNAseq]

Project description:Purpose: this study is to analyze the change of RNA splicing events after disruption of Protein Arginine Methyltranferase 5 (PRMT5) in Plasmodium falciparum. Methods: In this study, the transcriptomes of a PfPRMT5 gene knockout (KO) parasite line with its wildtype control were analyzed by RNAseq.Total RNA were harvested from the asexual parasites at four stages (ring, early trophozoite, late trophozoite, and schizont)(12h, 24h, 36h, and 46h post-invasion) using the Quick-RNA MiniPrep kit (Zymo Research). RNA sequencing libraries were prepared using the KAPA stranded RNA-seq library preparation kit (Roche) with 500 ng RNA from each sample. Illumina adapter sequence removal and quality trimming of reads were performed using Trimmomatic. Only reads that had a minimum length of 50 base pairs were retained. Reads were then mapped to the P. falciparum 3D7 strain reference genome with HISAT2. Results: This RNAseq analysis with strand-specific mRNA libraries from both ΔPfPRMT5 and WT lines showed that >90% of sequencing reads were of high quality for mapping to the P. falciparum genome with nearly 40 times of coverage. This allows us to analyze the change of alternative splicing events (alternative 5' splice site, alternative 3' splice site, retained intron and skipped exon). 800, 1056, 479, and 1158 alternative splicing events (alternative 5' splice site, alternative 3' splice site, retained intron and skipped exon) were altered in the DPfPRMT5 parasite line as compared to the WT line at four development stages, respectively (unpublished data). Conclusions: Collectively, this RNAseq provide a dataset for analysis of abnormal RNA splicing events in the ΔPfPRMT5 parasites.

2023-06-28 | GSE199366 | GEO

A germline mutation in SRRM2, a splicing factor gene, is implicated in papillary thyroid carcinoma predisposition

Project description:Papillary thyroid carcinoma (PTC) displays strong but so far largely uncharacterized heritability. Here we studied genetic predisposition in a family with six affected individuals. We genotyped all available family members and conducted whole exome sequencing of blood DNA from two affected individuals. Haplotype analysis and other genetic criteria narrowed our list of candidates to a germline variant in the serine/arginine repetitive matrix 2 gene (SRRM2). This heterozygous variant, c.1037C>T (Ser346Phe or S346F; rs149019598) cosegregated with PTC in the family. It was not found in 138 other PTC families. It was found in 7/1,170 sporadic PTC cases and in 0/1,404 controls (p=0.004). The encoded protein SRRM2 (also called SRm300) is part of the RNA splicing machinery. To evaluate the possibility that the S346F missense mutation affects alternative splicing, we compared RNA-Seq data in leukocytes from three mutation carriers and three controls. Significant differences in alternative splicing were identified for 1,642 exons, of which a subset of 7 exons was verified experimentally. The results confirmed a higher ratio of inclusion of exons in mutation carriers. These data suggest that the S346F mutation in SRRM2 predisposes to PTC by affecting alternative splicing of unidentified downstream target genes.

2017-08-14 | GSE68058 | GEO

SRRM2 Phase Separation Drives Assembly of Nuclear Speckle Subcompartments

Project description:Nuclear speckles (NSs) are nuclear biomolecular condensates that are postulated to arise through liquid-liquid phase separation (LLPS), although the detailed underlying forces driving NS formation remain elusive. SRRM2 and SON are 2 non-redundant scaffold proteins for NSs. How each individual protein governs assembly of NS protein network and the functional relationship between SRRM2 and SON are largely unknown. Here, we uncover immiscible multiphase of SRRM2 and SON within NSs. SRRM2 and SON are functionally independent, specifically regulating alternative splicing of subsets of mRNA targets, respectively. We further uncover that SRRM2 forms multicomponent liquid phase in cells to drive NS subcompartmentalization, which is reliant on homotypic interaction and heterotypic non-selective protein-RNA complex coacervation-driven multicomponent LLPS. SRRM2 RS domains form high-order oligomers, and can be replaced by oligomerizable synthetic modules, the serine residues within the RS domains, however, play an irreplaceable role in fine-tuning the liquidity of NSs.

2024-01-31 | GSE242898 | GEO

Comparison of PPIL1 knockdown in HEK293T cells compared to scrambled shRNA control

Project description:HEK293T cells transduced with shRNA from MISSION library TRCN0000420470 using lentiviral delivery system. HEK293T cells transduced with scrambled shRNA, gifted from Dr. Mauricio Reginato. Tara L Davis, S. RaElle Jackson, Beth Adams, Anh Trinh, Jenna Marinock, Peter Naranjo, NIcholas Fox, and Gueil Wong-Shing performed primary experimental contributions to cell lines, RNA/cDNA preparation, and validation, all Drexel University College of Medicine, Philadelphia, PA. Hetty Rodriguez and John Tobias performed Bioanalyzer and microarray expreriments, and initial data processing. Affiliation: Molecular Profiling Facility and Genomic Analysis Core Bioinformatics Group, University of Pennsylvania, Philadelphia, PA. Human PPIL1 is a cyclophilin, an enzyme that interconverts cis and trans isomers of proline. PPIL1 associates with the human spliceosome, the complex and dynamic machinery that removes intronic sequence from pre-messenger RNA (pre-mRNA). Nothing is known about the function of PPIL1 in regulating transcription or alternative splicing events. To understand the nuclear function of PPIL1, we knocked down PPIL1 in human cells. We characterized a set of alternative splicing and transcriptional events that are PPIL1-responsive. We used these splicing and transcriptional bioassays to show that PPIL1-responsive events are largely specific, even within the cyclophilin family.

2018-10-01 | GSE117381 | GEO

RNA-seq analysis of the WT and bcas2-KO zebrafish embryos at 3 dpf

Project description:The splicing factor Bcas2 is involved in several biological processes including tumorigenesis, gametogenesis, and hematopoiesis. The alternative splicing events and downstream genes regulated by Bcas2 have not yet been investigated at the transcriptome level in zebrafish. In this study, we conducted RNA-sequencing analysis on the WT and bcas2 knockout zebrafish embryos (3 dpf) to identify the global differentially expressed genes (DEGs) and differential splicing events (DSEs). 868 DEGs (293 up and 575 down) were identified and genes related to spliceosome, mRNA splicing, and mRNA processing were significantly upregulated, suggesting a negative feedback of the splicing pathway. Besides, 664 DSEs related to 593 genes were identified and sequence signature analysis of these DSEs revealed that the alternatively spliced exons affected by bcas2 knockout have relatively shorter length, longer upstream and downstream introns, and weaker 5’ or 3’ splicing sites, when compared with the control exons. Furthermore, we demonstrated that the exon 5 of ikzf1 gene, a transcription factor related to lymphocyte differentiation, was preferably skipped in the bcas2 knockout embryos, resulting in the deletion of 11 aa between the two conserved zinc finger domains of Ikzf1. Accordingly, several downstream genes, such as rasgrp2 and rgs2, were significantly downregulated and the lymphocyte generation was impaired in the bcas2 knockout embryos. Taken together, our work depicts the global changes of gene expression and alternative splicing caused by bcas2 knockout in zebrafish embryos and reveals an important role of Bcas2-regulated alternative splicing of ikzf1 in lymphoid hematopoiesis.

2024-06-01 | GSE246374 | GEO

ArgRS, MetRS, and SRRM2 dependent changes in mRNA splicing and exon usage

Project description:Arginine is involved in inflammation and amino acid signaling, in part through the mTORC1 pathway. In cell-based assays and in the mouse, we found that arginine regulates nuclear levels of arginyl-tRNA synthetase (ArgRS) and that nuclear ArgRS interacts and co-localizes with the Serine/Arginine Repetitive Matrix Protein 2 (SRRM2), a spliceosomal protein crucial for the formation of nuclear speckle condensates. Arginine depletion or ArgRS knock down, both of which decreased nuclear ArgRS levels, mobilized SRRM2 for trafficking from nuclear condensates and altered mRNA processing and splice junction usage while minimally affecting expression of other cellular RNAs. These splice junction changes included a subset that were inversely correlated with SRRM2 knock down induced changes and the affected genes encompassed components of the mTORC1 pathway. This inverse correlation suggests that the nuclear ArgRS-SRRM2 interaction regulates SRRM2 nuclear trafficking and alternative splicing in the physiological response to changed arginine levels resulting from inflammation.

2023-04-03 | GSE165513 | GEO

Dars2 is involved in mRNA splicing in mouse bone marrow hematopoietic stem and progenitor cells

Project description:Deletion of Dars2 in HSPCs largely impairs spliceosome function and suppresses the protein expression of Srsf3.We performed high-coverage mRNA-seq on lin- ckit+ (LK) cells from both WT and Dars2-KO mice, respectively, to characterize genome-wide alternative splicing (AS) events affected in Dars2-KO HSPCs. Globally, 3970 AS events were significantly changed by loss of Dars2 in HSPCs, including 2431 events in skipped exons (SEs), 516 events in retained introns (RIs), 375 events in mutually exclusive exons (MXEs), 340 events in alternative 3’ splice sites (A3SSs) and 308 events in alternative 5’ splice sites (A5SSs)

2023-09-25 | GSE213952 | GEO

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