ING5 affects mitosis and the DNA damage response in human and murine models
Date
2024-04-30
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Abstract
The INhibitor of Growth family (INGs 1-5) is part of lysine acetyltransferase and lysine deacetylase complexes. They are epigenetic readers that recruit these complexes to the H3K4Me3 mark of active transcription.. Several studies have implicated ING5 in stem cell maintenance in adult and cancer stem cells, cell cycle regulation, and DNA damage response pathways. Here, we investigate the roles of ING5 in two different systems: primary mouse embryonic fibroblasts (MEFs) derived from our Ing5-KO murine model and Brain Tumor Initiating Cells (BTIC cancer stem cells) derived from glioblastoma patients. We show that Ing5-KO MEFs have defects in the cell cycle, with cells accumulating in the G2/M phase of the cell cycle, and carry a higher DNA damage load than their WT counterparts. In addition, after exposure to oxidative stress Ing5-KO cells frequently have abnormal nuclei, defective mitosis and express increased levels of the p21 cyclin-dependent kinase inhibitor compared to WT. RNA-seq analysis of Ing5-KO MEFs revealed significant downregulation of the HOXA family of transcription factors and other transcription factors involved in development such as FOXD1, SOX5 and two transcription factors of the GATA family, indicating that ING5 is part of a network for the regulation of developmental transcription factors. ING5 was also detected on the promoters of SOX4 and GATA6 in primary human fibroblasts, established human embryonic kidney (HEK293) cells and a glioma stem cell.
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Keywords
Epigenetics, ING5, Cell cycle, Development
Citation
Estanislau Dantas, A. (2024). ING5 affects mitosis and the DNA damage response in human and murine models (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.