Nuclear Translocation of SRPKs Is Associated with 5-FU and Cisplatin Sensitivity in HeLa and T24 Cells
Serine/arginine protein kinases (SRPKs) phosphorylate proteins containing Arg/Ser dipeptides, which are essential for a wide range of cellular processes. A distinctive structural feature of SRPKs is the presence of a large internal spacer sequence that separates the bipartite kinase catalytic core and anchors the kinases in the cytoplasm. In this study, we found that exposing HeLa and T24 cells to DNA damage inducers triggers the nuclear translocation of SRPK1 and SRPK2. Interestingly, while nuclear SRPKs did not provide protection, they instead mediated the cytotoxic effects of genotoxic agents such as 5-fluorouracil (5-FU) and cisplatin. Our findings confirmed that kinase activity is crucial for SRPK nuclear entry; the selective SRPK1/2 inhibitor SRPIN340 blocked their nuclear accumulation, thereby reducing the cytotoxic effects of these drugs. Moreover, ATR/ATM-dependent phosphorylation of threonine 326 and serine 408 within the spacer domain of SRPK1 was necessary for its nuclear redistribution. Mutating either residue to alanine or inhibiting ATR/ATM kinase activity prevented SRPK1’s nuclear localization and conferred resistance to 5-FU treatment. These results suggest that SRPKs may play a significant role in connecting cellular signaling to DNA damage responses in eukaryotic cells.