MUS81 Inhibition Increases the Sensitivity to Therapy Effect in Epithelial Ovarian Cancer via Regulating CyclinB Pathway

Abstract

MUS81 is a key endonuclease involved in homologous recombination (HR) repair after DNA double-strand damage. Structure-specific endonucleases (SSEs) plays a crucial role in DNA replication, repair and transcription, and SSEs are also important for maintaining the secondary structure of DNA; therefore, their activity must be precisely controlled to ensure genome stability. We previously described that MUS81 expression was significantly correlated with CyclinB expression based on protein microarray analysis. CyclinB is a cell-cycle regulatory protein that has been shown to be involved in the activation of DNA damage repair checkpoints by inducing G2/M phase arrest, promoting apoptosis, and participating in the regulation of chemotherapeutic drug sensitivity by inducing nuclear degradation, as shown by immunofluorescence assays. In this study, MUS81-downregulated cells were generated using lentivirus-mediated RNAi. Our results demonstrated that the inhibition of MUS81 expression activated the CHK1 and CyclinB signaling pathways and sensitized ovarian cancer cells to X-ray and Olaparib treatment both in vitro and in vivo . MUS81 may be a potential therapeutic target for epithelial ovarian cancer (EOC).

Inhibition of MUS81 By siRNA Reverses Resistance to Cisplatin in Human Ovarian Cancer Cell Lines

“…In addition, a further investigation into the role of MUS81 in cellular response to anticancer treatment revealed that MUS81 lentivirus siRNA mediated knockdown in the colon cancer cell lines HCT116 and LS180 resulted in elevated cellular sensitivity to therapeutic drugs including cisplatin. This sensitisation was again mediated via the CHK1 signalling pathway followed by an S phase cell cycle arrest and an increase in cellular apoptosis [22][23][24][25][26] .…”

Resolvases, Dissolvases, and Helicases in Homologous Recombination: Clearing the Road for Chromosome Segregation

“…Genetic polymorphisms in MLH1 have also been associated with male infertility [178]. In addition, some of these DNA-remodeling enzymes, such as for example MUS81, are also emerging as potential targets in chemotherapeutic intervention [179][180][181][182]. Thus, advances in yeast studies have important implications in understanding the basis of human disorders linked to genome instability.…”

Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities

“…To circumvent resistance, therapies that include PARPi as an adjuvant to conventional chemotherapies have been tested and have sometimes cast promising results [ 129 , 137 ]. PARPi have also been combined with inhibitors for cell cycle checkpoint kinases such as ATR, CHK1, and WEE1 [ 138 , 139 ]; MUS81 nuclease inhibitors [ 140 ]; or signaling molecule inhibitors such as PI3K, AKT, or mTOR [ 141 ]. Inhibitors of alternative end-joining (Alt-EJ) polymerase theta are also under development as that appears to be the predominant repair choice for one-ended DSBs in HR-deficient cells [ 142 ].…”