RESUMO
XAB2 is a multi-functional protein participating processes including transcription, splicing, DNA repair and mRNA export. Here, we report POLR2A, the largest catalytic subunit of RNA polymerase II, 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-based quantitative proteomics 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 of XAB2 were critical for POLR2A expression by interacting with SNW1. 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.
Assuntos
Senescência Celular/genética , RNA Polimerases Dirigidas por DNA/genética , Íntrons/genética , Fatores de Transcrição/genética , Transcrição Gênica , Linhagem Celular , Linhagem Celular Tumoral , RNA Polimerases Dirigidas por DNA/metabolismo , Células HEK293 , Células HeLa , Humanos , Interferência de RNA , Splicing de RNA , Fatores de Processamento de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
OBJECTIVE: The present study aims to evaluate the relation between PON1 L55M polymorphism and ischemic stroke by a meta-analysis method. METHODS: English and Chinese databases were retrieved to find qualified studies; a random or fixed effects model was used to merge the odds ratio (OR); Q test was used to assess the heterogeneity among studies, and Egger's test and funnel plot were used for the assessment of publication bias. RESULTS: 14 studies were included in the meta-analysis; in total populations, there was no association between PON1 gene L55M polymorphism and ischemic stroke in additive, dominant, and recessive model, respectively. Furthermore, we did not found associations between L55M and ischemic stroke in Asian or Caucasian population. CONCLUSION: Available evidences suggested that L55M polymorphism had no effect on the risk of ischemic stroke. However, this conclusion needs further validation by larger sample and well-designed studies.