Cisplatin Induces Differential Expression of SnoRNAs and Affects Ribosome Methylation

Abstract

Although the chemotherapy drug cisplatin has been used in cancer treatment since the 1970s, a full understanding of the mechanisms by which it functions is still lacking. While the influence of DNA damage has been extensively studied as one cellular response to cisplatin, recent data indicate that non‐DNA targets, including RNA and proteins, also play important roles. To gain insight into the non‐DNA damage‐based effects induced by this drug, full RNA‐seq analysis of triple negative breast cancer MDA‐MB‐468 cells treated at therapeutic concentrations of cisplatin between 30 minutes and 24 hours was performed. The resulting data provide insight into the complex nature of the cellular response to cisplatin, including observation of novel responses. In one unexpected response, the expression of numerous snoRNAs decreases as early as 30 minutes post‐treatment. Located in the nucleolus, snoRNAs are necessary components in ribosome processing. A subgroup of the downregulated snoRNAs direct modification of helix 69 on the 28s ribosome, and correct modification of helix 69 is necessary for proper ribosomal formation and translation termination. Further quantification of methylation at helix 69 and other locations suggests that cisplatin induces changes in snoRNA expression and leads to dysregulation of rRNA modification, likely altering ribosome activity upon drug treatment through a nucleolar response.Support or Funding InformationNIH Graduate Training in Molecular Biology and Biophysics Grant (T32GM007759‐37), NSF (CHE‐1710721), and UO Bioinformatics and Genomics Masters ProgramThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.