CaMad2 Promotes Multiple Aspects of Genome Stability Beyond Its Direct Function in Chromosome Segregation

Abstract

Mad2 is a central component of the spindle assembly checkpoint required for accurate chromosome segregation. Additionally, in some organisms, Mad2 has roles in preventing mutations and recombination through the DNA damage response. In the fungal pathogen Candida albicans, CaMad2 has previously been shown to be required for accurate chromosome segregation, survival in high levels of hydrogen peroxide, and virulence in a mouse model of infection. In this work, we showed that CaMad2 promotes genome stability through its well-characterized role in promoting accurate chromosome segregation and through reducing smaller scale chromosome changes due to recombination and DNA damage repair. Deletion of MAD2 decreased cell growth, increased marker loss rates, increased sensitivity to microtubule-destabilizing drugs, and increased sensitivity to DNA damage inducing treatments. CaMad2-GFP localized to dots, consistent with a role in kinetochore binding, and to the nuclear periphery, consistent with an additional role in DNA damage. Furthermore, deletion of MAD2 increases growth on fluconazole, and fluconazole treatment elevates whole chromosome loss rates in the mad2∆/∆ strain, suggesting that CaMad2 may be important for preventing fluconazole resistance via aneuploidy.

Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

“…The deletion of a single allele of Mad2 gene results in a defective mitotic checkpoint in HCT116 cells and mouse embryonic fibroblasts [23]. In some organisms, Mad2 exhibits roles in preventing mutations/recombination through the DDR [32]. We investigated whether DNA damage and chromosomal aberrations in TpMs-depleted cells might be consistent with defective SAC by assessing the expression level of Mad2 and several checkpoint proteins of the mitotic spindle.…”

“…This connection suggests that the reduced TpMs level detected in human biopsies of various cancer types might cause chromosome aberrations in these cancers, similar to the ones we revealed to occur in vitro in cancer-derived cells. In vitro findings on TpMs and Mad2 suggest the need to extend the determination of TpMs levels to a major number of diverse cancer types accompanied by the determination of Mad2 level [32,36], with the purpose of identifying diverse patient phenotypes related to TpMs and Mad2 expression. We speculate that the level of TpMs and Mad2 proteins might be exploited as possible relevant biomarkers that are useful to obtain therapeutic interventions for patients bearing solid cancer.…”