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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

SUBMITTER: Xiaochun Yu

PROVIDER: PXD080922 | iProX | Thu Jul 09 00:00:00 GMT+01:00 2026

REPOSITORIES: iProX

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Project description:Alternative pre-messenger RNA splicing impacts development, physiology, and disease, but its regulation in humans is not well understood, partially due to the limited scale to which the expression of specific splicing events has been measured. We generated the first genome-scale expression compendium of human alternative splicing events using custom whole-transcript microarrays monitoring expression of 24,426 mutually exclusive alternative splicing event pairs in 48 diverse human samples. Over 11,700 genes and 9,500 splicing events were differentially expressed, providing a rich resource for studying splicing regulation. An unbiased, systematic screen of 21,760 4-mer to 7-mer words for cis-regulatory motifs identified 143 RNA 'words' enriched near regulated cassette exons, including six clusters of motifs represented by UCUCU, UGCAUG, UGCU, UGUGU, UUUU, and AGGG, which map to trans-acting regulators PTB, Fox, Muscleblind, CELF/CUG-BP, TIA-1, and hnRNP F/H, respectively. Each cluster showed a distinct pattern of genomic location and tissue specificity. For example, UCUCU occurs 110 to 35 nucleotides preceding cassette exons upregulated in brain and striated muscle but depleted in other tissues. UCUCU and UGCAUG appear to have similar function but independent action, occurring 5' and 3', respectively, of 33% of the cassette exons upregulated in skeletal muscle but co-occurring for only 2%. Keywords: multiple tissue comparison PolyA+ purified RNA pooled from multiple donors of a single human tissue type (e.g. cerebellum) were amplified with random primers and hybridized on a two-color ink-jet oligonucletodie microarray (17 array set) against a common reference pool, comprising ~20 normal adult tissue pools, on custom microarray patterns containing probes to monitor every exon and exon-exon junction in transcript databases, patent databases, and predicted from mouse transcripts. Data were analyzed for gene expression (the average of multiple probes), exon and junction expression, and splice form proportionality (see paper).

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

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