The RNA processing factors THRAP3 and BCLAF1 promote the DNA damage response through selective mRNA splicing and nuclear export

Abstract

AbstractmRNA splicing and export plays a key role in the regulation of gene expression, with recent evidence suggesting an additional layer of regulation of gene expression and cellular function through the selective splicing and export of genes within specific pathways. Here we describe a role for the RNA processing factors THRAP3 and BCLAF1 in the regulation of the cellular DNA damage response (DDR) pathway, a key pathway involved in the maintenance of genomic stability and the prevention of oncogenic transformation. We show that loss of THRAP3 and/or BCLAF1 leads to sensitivity to DNA damaging agents, defective DNA repair and genomic instability. Additionally, we demonstrate that this phenotype can be at least partially explained by the role of THRAP3 and BCLAF1 in the selective mRNA splicing and export of transcripts encoding key DDR proteins, including the ATM kinase. Moreover, we show that cancer associated mutations within THRAP3 result in deregulated processing of THRAP3/BCLAF1-regulated transcripts and consequently defective DNA repair. Taken together, these results suggest that THRAP3 and BCLAF1 mutant tumors may be promising targets for DNA damaging chemotherapy.

Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation

“…Treatment with cisplatin, mitomycin C, irinotecan, doxorubicin, etoposide and 5-FU, all resulted in cytosolic dsDNA ( Figure 1B). Quantification using a previously described image compartmentalisation and quantification algorithm [13], confirmed that cytosolic dsDNA significantly increased following treatment with cisplatin, mitomycin C, irinotecan, doxorubicin, etoposide and 5-FU, in comparison to vehicle treated control cells ( Figure 1C). dsDNAse treatment was used as a control to confirm quantified fluorescence signal was dsDNA (***=p≤0.001).…”

Human proteins that interact with RNA/DNA hybrids

“…The resulting combinations likely provide surfaces that facilitate binding to RNA/DNA hybrids. Other protein complexes include RPA1, RNase H1 (Nguyen et al 2017), and THRAP3/BCLAF1 (Vohhodina et al 2017). Thus, our pull-down assays identify direct RNA-protein and indirect RNA-protein interactions mediated by protein-protein interactions.…”

Heat Shock Protein 90α–Dependent B‐Cell‐2–Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto‐Oncogene c‐MYC mRNA Stability

“…( ) In vitro studies also implicated Bclaf1 in pathways linking transcriptional events to cell death, DNA damage, or autophagy. ( ) Although most studies suggest that Bclaf1 acts as a tumor suppressor, more‐recent studies provided evidence for an oncogenic function of Bclaf1 in bladder and colon cancer. ( ) Thus, the function of Bclaf1 in carcinogenesis is controversial and still needs to be further explored in different tumor tissues.…”