Year-end Sale % OFF 
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.
Highlights
Many chemicals with a mutagenic mode of action interact with DNA, causing changes in its structure; thereby blocking nuclear processes such as DNA replication, transcription, recombination and repair [1]
While Rad50 binds the DNA ends and holds them in close proximity, Nbs1 is essential for nuclear translocation of the Mre11-Rad50 complex; it interacts with ATM kinase and several other binding partners in DNA damage response [18]
MRN complex is the major sensor of double strand breaks (DSBs) and is essential for the repair of DNA damage, little is known about its role in human cells treated with cisplatin
Summary
Many chemicals with a mutagenic mode of action interact with DNA, causing changes in its structure; thereby blocking nuclear processes such as DNA replication, transcription, recombination and repair [1]. The widely used anticancer drug cisplatin and its derivatives kill cancer cells by creating intrastrand and/ or interstrand cross-links (ICLs) in DNA; thereby inhibit both replication and transcription [2, 3]. The cells from bacteria, yeast and mammals remove ICL adducts from their genomic DNA through a complex network of multiple DNA damage response and repair pathways, www.oncotarget.com including mismatch repair, homologous recombination (HR), double strand break (DSB) repair, transcription coupled nucleotide excision repair and base excision repair [7,8,9,10]. A review of current literature indicates that the Fanconi anaemia pathway of ICL repair involves 22 ‘FANC’ enzymes and accessory proteins; defects in these components cause Fanconi anaemia, a genetic disorder characterized by bone marrow failure and a predisposition to cancer [11, 12]. A growing body of evidences indicates that FA proteins function in the repair of DNA damage caused by certain types of chemotherapeutic drugs [13, 14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
