Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.130
Inactivation of Mad2B Enhances Apoptosis in Human Cervical Cancer Cell Line upon Cisplatin-Induced DNA Damage
Ju Hwan Kim1,*, Hak Rim Kim1 and Rajnikant Patel2
1Department of Pharmacology, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea
2Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK
*E-mail: jhkim731@dankook.ac.kr
Tel: +82-41-550-3797, Fax: +82-41-559-7940
Received: October 12, 2022; Revised: December 1, 2022; Accepted: December 19, 2022; Published online: January 16, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Mad2B (Mad2L2), the human homolog of the yeast Rev7 protein, is a regulatory subunit of DNA polymerase ζ that shares sequence similarity with the mitotic checkpoint protein Mad2A. Previous studies on Mad2B have concluded that it is a mitotic checkpoint protein that functions by inhibiting the anaphase-promoting complex/cyclosome (APC/C). Here, we demonstrate that Mad2B is activated in response to cisplatin-induced DNA damage. Mad2B co-localizes at nuclear foci with DNA damage markers, such as proliferating cell nuclear antigen and gamma histone H2AX (γ-H2AX), following cisplatin-induced DNA damage. However, unlike Mad2A, the binding of Mad2B to Cdc20 does not inhibit the activity of APC/C in vitro. In contrast to Mad2A, Mad2B does not localize to kinetochores or binds to Cdc20 in spindle assembly checkpoint-activated cells. Loss of the Mad2B protein leads to damaged nuclei following cisplatin-induced DNA damage. Mad2B/Rev7 depletion causes the accumulation of damaged nuclei, thereby accelerating apoptosis in human cancer cells in response to cisplatin-induced DNA damage. Therefore, our results suggest that Mad2B may be a critical modulator of DNA damage response.
Keywords: Mad2B, Cell cycle, Cisplatin, DNA damage, Apoptosis, Cancer


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