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Increased double strand breaks in diabetic β-cells with a p21 response that limits apoptosis

Vanessa S Y Tay1, Surabhi Devaraj1, Tracy Koh2

  • 1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.

Scientific Reports
|December 20, 2019
PubMed

Insights

DNA damage response (DDR) in beta cells is crucial for type-2 diabetes. P21 overexpression prevents apoptosis from DNA strand breaks, but its inhibition increases beta cell death.

Area of Science:

  • Cellular biology
  • Diabetes research
  • Molecular genetics

Background:

  • DNA damage and response (DDR) in pancreatic beta cells are understudied in type-2 diabetes.
  • DNA strand breaks (DSBs) are implicated in beta cell dysfunction.

Purpose of the Study:

  • To investigate the role of p21 in beta cell DNA damage response (DDR).
  • To determine the effect of p21 inhibition on beta cell apoptosis under DNA damage conditions.

Main Methods:

  • Comet assays and immunofluorescence (γH2AX, 53bp1) to detect DSBs in mouse beta cells.
  • Gene expression analysis (gadd45a, p21) in doxorubicin-treated MIN6 cells.
  • Western blot for cleaved caspase3.
  • Pharmacological inhibition of p21 using UC2288.

Main Results:

  • Diabetic mouse beta cells exhibit increased DSBs compared to non-diabetic controls.
  • Doxorubicin-induced DNA damage in MIN6 cells mimics DDR observed in diabetic beta cells, with p21 overexpression.
  • p21 inhibition significantly increased beta cell apoptosis under DNA damage conditions.

Conclusions:

  • DSBs trigger p21 overexpression and the p53/p21 pathway in beta cells.
  • p21 plays a protective role against apoptosis in beta cells experiencing DNA damage.
  • Targeting p21 inhibition could exacerbate beta cell loss in type-2 diabetes.

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