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Role of POLR2A in kidney response to DNA damage

ABSTRACT: The role of POLR2A/RPB1 in kidney proximal tubule responses to DNA damage-induced acute kidney injury is unknown. We undertook treatment of HK2 cells with the DNA damaging agent aristolochic acid, with or without knockdown of POLR2A to determine the role of RPB1 in kidney cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282647 | GEO | 2025/05/08

REPOSITORIES: GEO

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Proximal tubular transcriptional response to aristolochic acid

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Role of POLR2A in kidney response to DNA damage

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XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence

Project description:XAB2 is a multi-functional protein participating processes including transcription, splicing, DNA repair and mRNA export. Here we report POLR2A as a major target gene down-regulated after XAB2 depletion. XAB2 depletion led to severe splicing defects of POLR2A with significant intron retention. Such defects resulted in substantial loss of POLR2A at RNA and protein levels, which further impaired global transcription. Treatment of splicing inhibitor madrasin induced similar reduction of POLR2A. Screen using TMT identified several proteins involved in mRNA surveillance including Dom34 with elevated expression. Inhibition of translation or depletion of Dom34 rescued the expression of POLR2A by stabilizing its mRNA. Immuno-precipitation further confirmed that XAB2 associated with spliceosome components important to POLR2A expression. Domain mapping revealed that TPR motifs 2-4 and 11-12 of XAB2 were critical for POLR2A expression. Finally we showed POLR2A mediated cell senescence caused by XAB2 deficiency. Depletion of XAB2 or POLR2A induced cell senescence by up-regulation of p53 and p21, re-expression of POLR2A after XAB2 depletion alleviated cellular senescence. These data together support that XAB2 serves as a guardian of POLR2A expression to ensure global gene expression and antagonize cell senescence.

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