1. Academic Validation
  2. XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence

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

  • Nucleic Acids Res. 2019 Sep 5;47(15):8239-8254. doi: 10.1093/nar/gkz532.
Shuai Hou 1 Dajun Qu 1 Yue Li 2 Baohui Zhu 1 Dapeng Liang 1 Xinyue Wei 1 Wei Tang 3 Qian Zhang 1 Jiaojiao Hao 1 Wei Guo 1 Weijie Wang 1 Siqi Zhao 1 Qi Wang 1 Sikandar Azam 1 Misbah Khan 1 Haidong Zhao 2 Liye Zhang 3 Haixin Lei 1
Affiliations

Affiliations

  • 1 Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
  • 2 Breast Disease and Reconstruction Center, Breast Cancer Key Lab of Dalian, Second Affiliated Hospital, Dalian Medical University, Dalian, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Abstract

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.

Figures
Products