Evidence for functional and regulatory cross-talk between Wnt/?-catenin signalling and Mre11-Rad50-Nbs1 complex in the repair of cisplatin-induced DNA cross-links.
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ABSTRACT: The canonical Wnt/?-catenin signalling pathway plays a crucial role in a variety of functions including cell proliferation and differentiation, tumorigenic processes and radioresistance in cancer cells. The Mre11-Rad50-Nbs1 (MRN) complex has a pivotal role in sensing and repairing DNA damage. However, it remains unclear whether a connection exists between Wnt/?-catenin signalling and the MRN complex in the repair of cisplatin-induced DNA interstrand cross-links (ICLs). Here, we report that (1) cisplatin exposure results in a significant increase in the levels of MRN complex subunits in human tumour cells; (2) cisplatin treatment stimulates Wnt/?-catenin signalling through increased ?-catenin expression; (3) the functional perturbation of Wnt/?-catenin signalling results in aberrant cell cycle dynamics and the activation of DNA damage response and apoptosis; (4) a treatment with CHIR99021, a potent and selective GSK3? inhibitor, augments cisplatin-induced cell death in cancer cells. On the other hand, inactivation of the Wnt/?-catenin signalling with FH535 promotes cell survival. Consistently, the staining pattern of ?H2AX-foci is significantly reduced in the cells exposed simultaneously to cisplatin and FH535; and (5) inhibition of Wnt/?-catenin signalling impedes cisplatin-induced phosphorylation of Chk1, abrogates the G2/M phase arrest and impairs recombination-based DNA repair. Our data further show that Wnt signalling positively regulates the expression of ?-catenin, Mre11 and FANCD2 at early time points, but declining thereafter due to negative feedback regulation. These results support a model wherein Wnt/?-catenin signalling and MRN complex crosstalk during DNA ICL repair, thereby playing an important role in the maintenance of genome stability.
SUBMITTER: Pasadi S
PROVIDER: S-EPMC7646826 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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