Resistance to Chemotherapeutic 5-Fluorouracil Conferred by Modulation of Heterochromatic Integrity through Ino80 Function in Fission Yeast

• Published in: International journal of molecular sciences 2023-06, Vol.24 (13), p.10687
• Main Authors: Lim, Kim Kiat, Koh, Nathaniel Zhi Hao, Zeng, Yi Bing, Chuan, Jun Kai, Raechell, Raechell, Chen, Ee Sin
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; 5-FU; Apoptosis; Biosynthesis; Cancer; Cell cycle; Cell growth; chemotherapeutic drug; Chemotherapy; Chromatin; Chromatin remodeling; Chromosomes; Disruption; DNA damage; DNA repair; Enzymes; fission yeast; Fluorouracil; Fluorouracil - metabolism; Fluorouracil - pharmacology; Gene expression; Genes; Heterochromatin; Heterochromatin - metabolism; Kinases; Metabolites; Mutants; Nucleotides; Oxidative phosphorylation; Phosphorylation; resistance; Resistance factors; RNA; RNA Interference; RNA polymerase; RNA processing; RNA-mediated interference; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Schizosaccharomyces pombe; Schizosaccharomyces pombe Proteins - genetics; Schizosaccharomyces pombe Proteins - metabolism; Transcription Factors - metabolism; Yeast
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241310687

5-Fluorouracil (5-FU) is a conventional chemotherapeutic drug widely used in clinics worldwide, but development of resistance that compromises responsiveness remains a major hurdle to its efficacy. The mechanism underlying 5-FU resistance is conventionally attributed to the disruption of nucleotide synthesis, even though research has implicated other pathways such as RNA processing and chromatin dysregulation. Aiming to clarify resistance mechanisms of 5-FU, we tested the response of a collection of fission yeast ( ) null mutants, which confer multiple environmental factor responsiveness (MER). Our screen identified disruption of membrane transport, chromosome segregation and mitochondrial oxidative phosphorylation to increase cellular susceptibility towards 5-FU. Conversely, we revealed several null mutants of Ino80 complex factors exhibited resistance to 5-FU. Furthermore, attenuation of Ino80 function via deleting several subunit genes reversed loss of chromosome-segregation fidelity in 5-FU in the loss-of-function mutant of the Argonaute protein, which regulates RNA interference (RNAi)-dependent maintenance of pericentromeric heterochromatin. Our study thus uncovered a critical role played by chromatin remodeling Ino80 complex factors in 5-FU resistance, which may constitute a possible target to modulate in reversing 5-FU resistance.