Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Inactivation of Mad2B Enhances Apoptosis in Human Cervical Cancer Cell Line upon Cisplatin-Induced DNA Damage

  • Ju Hwan Kim (Department of Pharmacology, College of Medicine, Dankook University) ;
  • Hak Rim Kim (Department of Pharmacology, College of Medicine, Dankook University) ;
  • Rajnikant Patel (Department of Molecular and Cell Biology, University of Leicester)
  • Received : 2022.10.12
  • Accepted : 2022.12.19
  • Published : 2023.05.01
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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

Acknowledgement

We would like to thank Dr. Pablo Lara-Gonzalez to help in vitro ubiquitylation assay. This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) (NRF-2022R1A2C1012144 to J.H.K.).

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