PT  - JOURNAL ARTICLE
AU  - Gabriel Brawerman
AU  - Peter J. Thompson
TI  - DNA damage induces senescent phenotypes in mouse NIT1 beta cells and human islets
AID  - 10.1101/2021.06.07.447428
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.06.07.447428
4099  - http://biorxiv.org/content/early/2021/06/10/2021.06.07.447428.short
4100  - http://biorxiv.org/content/early/2021/06/10/2021.06.07.447428.full
AB  - Pancreatic beta cells are essential endocrine cells in the islets of Langerhans that respond to increases in blood glucose by secreting insulin and their dysfunction and death drives the development of diabetes. Beta cell senescence involving a DNA damage response (DDR) was recently shown to contribute to the pathogenesis of Type 1 Diabetes (T1D), however, a basic mechanistic understanding of how senescence develops in beta cells is lacking. Here, we investigated senescent phenotypes arising in the mouse beta cell line NIT1 derived from the T1D susceptible nonobese diabetic (NOD) mouse strain and the transcriptome response in human islets after induction of DNA damage. Sub-lethal DNA damage in NIT1 cells led to several classical hallmarks of senescence including the DDR, growth arrest, enlarged flattened morphology and a senescence-associated secretory phenotype (SASP) resembling what occurs during T1D. RNA-seq analysis on human islets with DNA double-strand break damage revealed a coordinated p53-p21 transcriptional response and upregulation of genes involved in prosurvival signaling and SASP. Taken together, these findings suggest that some of the phenotypes of mouse and human beta cell senescence during T1D can be induced by DNA damage in NIT1 cells and human islets in culture.HighlightsDNA double-strand breaks induce senescence in the NIT1 beta cell lineDNA damage induces a p53-p21 transcriptional response in human isletsDNA damage can be used to model senescent phenotypes in mouse and human beta cell sourcesCompeting Interest StatementThe authors have declared no competing interest.