Oncotarget

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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

Sanjeev Pasadi and Kalappa Muniyappa _

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Oncotarget. 2020; 11:4028-4044. https://doi.org/10.18632/oncotarget.27777

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Abstract

Sanjeev Pasadi1 and Kalappa Muniyappa1

1 Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India

Correspondence to:

Kalappa Muniyappa,email: kmbc@iisc.ac.in

Keywords: cancer; cisplatin resistance; cisplatin-induced DNA crosslinks; Wnt/β-catenin signalling; Mre11–Rad50–Nbs1 complex

Received: May 07, 2020     Accepted: September 10, 2020     Published: November 03, 2020

Copyright: © 2020 Pasadi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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/β-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 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.


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