Work

The Yin and Yang of Modulating β-Cell DNA Damage Response and Functional Mass

Year: 2022

Type: article

Abstract: Pancreatic b-cells secrete the hormone insulin, which is essential to maintain systemic glucose homeostasis.b-Cell insufficiency due to impaired function, loss of identity, and increased cell death is central to the pathogenesis of diabetes.b-Cells in adult life are postmitotic, with a limited capacity to replicate and expand, and this ability further declines with age (1-3).Cells like the adult b-cell must deploy robust strategies, such as efficient repair of DNA damage, to ensure their genomic integrity and survival throughout their lifespans.DNA damage can alter the genomic output (e.g., transcription) and trigger genomic instability, which can lead to cellular dysfunction and ultimately death.Cells possess a battery of mechanisms, collectively called the DNA damage response (DDR), that sense and repair DNA damage (4).The DDR is also intimately linked with cell cycle control, with the cell cycle checkpoints also serving as checkpoints for DNA structure (5).Although emerging evidence suggests that prolonged DDR can trigger b-cell dysfunction and death, very little is known about the molecular control of DDR in b-cells and its impact on b-cell proliferation and function.In this issue of Diabetes, Pec ¸anha et al. (6) provide insights in this area and uncover a novel mechanistic link between b-cell replication and DDR that is defective in diabetes.The authors observed that b-cells of the insulin-resistant young db/db mice display profound alterations in genes associated with cell cycle and DDR pathways and identified the polycomb protein Yin Yang 1 (YY1) as a shared regulator of the two aspects.Notably, they found that YY1 levels were reduced in b-cells from diabetic db/db mice, mice fed a high-fat diet, and human donors with type 2 diabetes (T2D).They also leveraged multiple models of b-cell-specific Yy1 deletion

Source: Diabetes

DOI: 10.2337/dbi22-0010

Authors: Jason M. Spaeth, Sangeeta Dhawan