Vohhodina Jekaterina, Barros Eliana M, Savage Abigail L, Liberante Fabio G, Manti Lorenzo, Bankhead Peter, Cosgrove Nicola, Madden Angelina F, Harkin D Paul, Savage Kienan I
Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK.
Dipartimento di Fisica 'E Pancini', Università di Napoli Federico II, Monte S. Angelo, 80126 Napoli, Italy.
Nucleic Acids Res. 2017 Dec 15;45(22):12816-12833. doi: 10.1093/nar/gkx1046.
mRNA 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.
mRNA剪接和输出在基因表达调控中起关键作用，最近有证据表明，通过特定途径内基因的选择性剪接和输出，基因表达和细胞功能存在另一层调控。在此，我们描述了RNA加工因子THRAP3和BCLAF1在细胞DNA损伤反应（DDR）途径调控中的作用，DDR途径是维持基因组稳定性和预防致癌转化的关键途径。我们发现，THRAP3和/或BCLAF1的缺失会导致对DNA损伤剂敏感、DNA修复缺陷和基因组不稳定。此外，我们证明，这种表型至少可以部分由THRAP3和BCLAF1在选择性mRNA剪接和输出编码关键DDR蛋白（包括ATM激酶）的转录本中的作用来解释。此外，我们表明，THRAP3内的癌症相关突变会导致THRAP3/BCLAF1调控的转录本加工失调，从而导致DNA修复缺陷。综上所述，这些结果表明，THRAP3和BCLAF1突变肿瘤可能是DNA损伤化疗的有希望的靶点。
