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Inactivation of Mad2B Enhances Apoptosis in Human Cervical Cancer Cell Line upon Cisplatin-Induced DNA Damage

Ju Hwan Kim1, Hak Rim Kim1, Rajnikant Patel2

  • 1Department of Pharmacology, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea.

Biomolecules & Therapeutics
|January 16, 2023
PubMed

Insights

Mad2B, a DNA polymerase ζ subunit, is activated by cisplatin DNA damage, localizing to nuclear foci. Unlike Mad2A, Mad2B does not inhibit APC/C, but its depletion accelerates apoptosis in cancer cells.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Mad2B (Mad2L2) is a regulatory subunit of DNA polymerase ζ.
  • Previous studies suggested Mad2B functions as a mitotic checkpoint protein inhibiting the anaphase-promoting complex/cyclosome (APC/C).

Purpose of the Study:

  • To investigate Mad2B's role in DNA damage response.
  • To clarify Mad2B's function in relation to DNA damage and APC/C activity.

Main Methods:

  • Assessing Mad2B activation and localization following cisplatin treatment.
  • Evaluating Mad2B's interaction with Cdc20 and its effect on APC/C activity in vitro.
  • Analyzing the consequences of Mad2B depletion on DNA damage and apoptosis in human cancer cells.

Main Results:

  • Mad2B is activated by cisplatin-induced DNA damage and co-localizes with DNA damage markers.
  • Mad2B binding to Cdc20 does not inhibit APC/C activity in vitro.
  • Mad2B does not localize to kinetochores or bind Cdc20 during spindle assembly checkpoint activation.
  • Loss of Mad2B leads to increased nuclear damage and accelerated apoptosis in response to cisplatin.

Conclusions:

  • Mad2B is not a mitotic checkpoint protein inhibiting APC/C.
  • Mad2B plays a critical role in the DNA damage response pathway.
  • Mad2B modulation may represent a therapeutic strategy for enhancing cancer treatment efficacy.
Keywords:
ApoptosisCancerCell cycleCisplatinDNA damageMad2B

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