Pasadi, S and Muniyappa, K (2020) Evidence for functional and regulatory cross-talk between Wnt/ β-catenin signalling and Mre11–Rad50–Nbs1 complex in the repair of cisplatin-induced DNA cross-links. In: Oncotarget, 11 (44). pp. 4028-4044.
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Abstract
The canonical Wnt/β-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/β-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/β-catenin signalling through increased β-catenin expression; (3) the functional perturbation of Wnt/β-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 GSK3β inhibitor, augments cisplatin-induced cell death in cancer cells. On the other hand, inactivation of the Wnt/β-catenin signalling with FH535 promotes cell survival. Consistently, the staining pattern of γH2AX-foci is significantly reduced in the cells exposed simultaneously to cisplatin and FH535; and (5) inhibition of Wnt/βcatenin 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 β-catenin, Mre11 and FANCD2 at early time points, but declining thereafter due to negative feedback regulation. These results support a model wherein Wnt/β-catenin signalling and MRN complex crosstalk during DNA ICL repair, thereby playing an important role in the maintenance of genome stability. © 2020 Pasadi and Muniyappa.
| Item Type: | Journal Article |
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| Publication: | Oncotarget |
| Publisher: | Impact Journals LLC |
| Additional Information: | The copyright for this article belongs to The Authors. |
| Keywords: | beta catenin; cisplatin; double strand break repair protein MRE11; nibrin; Rad50 protein; Wnt protein, antineoplastic activity; apoptosis; Article; cell cycle; cell cycle progression; cell viability; controlled study; cytotoxicity; DNA cross linking; DNA damage response; DNA repair; FANCD2 gene; G2 phase cell cycle checkpoint; gene; gene expression; human; human cell; protein phosphorylation; signal transduction; sister chromatid; upregulation; Western blotting; Wnt signaling |
| Department/Centre: | Division of Biological Sciences > Biochemistry |
| Date Deposited: | 10 Jan 2023 09:41 |
| Last Modified: | 10 Jan 2023 09:41 |
| URI: | https://eprints.iisc.ac.in/id/eprint/79017 |
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