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Title: Increased double strand breaks in diabetic β-cells with a p21 response that limits apoptosis
Authors: Tay, VSY
Devaraj, S
Koh, T
Ke, G
Crasta, KC 
Ali, Y
Keywords: Animals
Cell Line
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p21
DNA Breaks, Double-Stranded
DNA Repair
Diabetes Mellitus, Experimental
Gene Expression Regulation
Insulin-Secreting Cells
Mice, Inbred C57BL
Time Factors
Issue Date: 1-Dec-2019
Publisher: Springer Science and Business Media LLC
Citation: Tay, VSY, Devaraj, S, Koh, T, Ke, G, Crasta, KC, Ali, Y (2019-12-01). Increased double strand breaks in diabetic β-cells with a p21 response that limits apoptosis. Scientific Reports 9 (1) : 19341-. ScholarBank@NUS Repository.
Abstract: DNA damage and DNA damage response (DDR) pathways in β-cells have received little attention especially in the context of type-2 diabetes. We postulate that p21 plays a key role in DDR by preventing apoptosis, associated through its overexpression triggered by DNA stand breaks (DSBs). Our results show that β-cells from chronic diabetic mice had a greater extent of DSBs as compared to their non-diabetic counterparts. Comet assays and nuclear presence of γH2AX and 53bp1 revealed increased DNA DSBs in 16 weeks old (wo) db/db β-cells as compared to age matched non-diabetic β-cells. Our study of gene expression changes in MIN6 cell line with doxorubicin (Dox) induced DNA damage, showed that the DDR was similar to primary β-cells from diabetic mice. There was significant overexpression of DDR genes, gadd45a and p21 after a 24-hr treatment. Western blot analysis revealed increased cleaved caspase3 over time, suggesting higher frequency of apoptosis due to Dox-induced DNA strand breaks. Inhibition of p21 by pharmacological inhibitor UC2288 under DNA damage conditions (both in Dox-induced MIN6 cells and older db/db islets) significantly increased the incidence of β-cell apoptosis. Our studies confirmed that while DNA damage, specifically DSBs, induced p21 overexpression in β-cells and triggered the p53/p21 cellular response, p21 inhibition exacerbated the frequency of apoptosis.
Source Title: Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/s41598-019-54554-8
Appears in Collections:Staff Publications

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