| First Author | Tay VSY | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 19341 |
| PubMed ID | 31852915 | Mgi Jnum | J:297844 |
| Mgi Id | MGI:6479326 | Doi | 10.1038/s41598-019-54554-8 |
| Citation | Tay VSY, et al. (2019) Increased double strand breaks in diabetic beta-cells with a p21 response that limits apoptosis. Sci Rep 9(1):19341 |
| abstractText | DNA damage and DNA damage response (DDR) pathways in beta-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 beta-cells from chronic diabetic mice had a greater extent of DSBs as compared to their non-diabetic counterparts. Comet assays and nuclear presence of gammaH2AX and 53bp1 revealed increased DNA DSBs in 16 weeks old (wo) db/db beta-cells as compared to age matched non-diabetic beta-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 beta-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 beta-cell apoptosis. Our studies confirmed that while DNA damage, specifically DSBs, induced p21 overexpression in beta-cells and triggered the p53/p21 cellular response, p21 inhibition exacerbated the frequency of apoptosis. |
