Safeguarding genomic integrity in beta-cells: implications for beta-cell differentiation, growth, and dysfunction.
Publication Year:
2024
PubMed ID:
39364746
Public Summary:
High blood glucose is the hallmark of diabetes which is either due to insufficient quantity of insulin-producing beta-cells in the pancreas and/or due to their poor function such that beta-cells cannot accurately sense blood glucose levels and release sufficient insulin. Majority of the beta-cells that the human body requires for its entire lifetime are produced within 5 years of birth, in a process that involves self-renewal by cell division. This is followed by a period during which the newly divided beta-cells acquire the ability to secrete optimum insulin in response to changing blood glucose levels. The process of cell division renders the genetic material highly vulnerable to damage (DNA damage), which if unrepaired can permanently halt cell division, or lead to beta-cell dysfunction and death.
While it is known that DNA damage is a key driver for beta-cell defects in diabetes, very little is known about how beta-cells protect themselves against these damages, repair them, and ensure the stability of the genetic material especially in early life as beta-cells actively divide. DNA damage is also one of the main bottlenecks of stem-cell derived therapies for diabetes as it can lead to poor function after transplantation as well as increase the risk of cancer. In this invited review, we focus on the effect of DNA damage on maintaining the function and survival in beta-cells. We also discuss on how changes in nutrition, growth, sleep-wake cycle during childhood impact function and survival of beta-cells in adulthood. Finally, we highlight key gaps in our understanding of beta-cell DNA integrity and discuss emerging areas of interest. This review was a great opportunity for me to provide a detailed discussion on the rationale behind my CIRM funded study trying to establish the role of a DNA binding protein complex called Cohesins in protecting beta-cell DNA and aid in its growth and long-term function.
Scientific Abstract:
The maintenance of optimal glucose levels in the body requires a healthy reserve of the insulin producing pancreatic beta-cells. Depletion of this reserve due to beta-cell dysfunction and death results in development of diabetes. Recent findings highlight unresolved DNA damage as a key contributor to beta-cell defects in diabetes. Beta-cells face various stressors and metabolic challenges throughout life, rendering them susceptible to DNA breaks. The post-mitotic, long-lived phenotype of mature beta-cells further warrants robust maintenance of genomic integrity. Failure to resolve DNA damage during beta-cell development, therefore, can result in an unhealthy reserve of beta-cells and predispose to diabetes. Yet, the molecular mechanisms safeguarding beta-cell genomic integrity remain poorly understood. Here, we focus on the significance of DNA damage in beta-cell homeostasis and postulate how cellular expansion, epigenetic programming, and metabolic shifts during development may impact beta-cell genomic integrity and health. We discuss recent findings demonstrating a physiological role for DNA breaks in modulating transcriptional control in neurons, which share many developmental programs with beta-cells. Finally, we highlight key gaps in our understanding of beta-cell genomic integrity and discuss emerging areas of interest.
