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.

Content Provider	Europe PMC
Author	Pasadi, Sanjeev Muniyappa, Kalappa
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.
Journal	Oncotarget
Volume Number	11
PubMed Central reference number	PMC7646826
Issue Number	44
PubMed reference number	33216839
e-ISSN	19492553
DOI	10.18632/oncotarget.27777
Language	English
Publisher	Impact Journals LLC
Publisher Date	2020-11-03
Access Restriction	Open
Rights License	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. Copyright: © 2020 Pasadi et al.
Subject Keyword	cancer cisplatin resistance cisplatin-induced DNA crosslinks Wnt/β-catenin signalling Mre11–Rad50–Nbs1 complex
Content Type	Text
Resource Type	Article
Subject	Oncology