Sneha S Varghese, Alessandro Giovanni Hernandez-De La Peña, Sangeeta Dhawan
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引用次数: 0
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.
要维持体内最佳的血糖水平,就需要有一个健康的胰岛素分泌胰岛β细胞储备。由于β细胞功能障碍和死亡导致这种储备消耗殆尽,从而引发糖尿病。最近的研究结果表明,未解决的 DNA 损伤是导致糖尿病β细胞缺陷的关键因素。β细胞在整个生命过程中面临着各种压力和新陈代谢的挑战,使它们很容易发生DNA断裂。成熟β细胞的有丝分裂后长寿命表型进一步要求对基因组完整性进行强有力的维护。因此,如果不能在β细胞发育过程中解决DNA损伤问题,就会导致β细胞储备不健康,并容易诱发糖尿病。然而,人们对保护β细胞基因组完整性的分子机制仍然知之甚少。在这里,我们将重点关注 DNA 损伤在β细胞稳态中的意义,并推测细胞扩增、表观遗传编程和发育过程中的代谢转变可能会如何影响β细胞基因组的完整性和健康。我们讨论了最近的研究结果,这些结果表明DNA断裂在调节神经元转录控制中的生理作用,而神经元与β细胞共享许多发育程序。最后,我们强调了我们在了解β细胞基因组完整性方面存在的主要差距,并讨论了新出现的关注领域。
期刊介绍:
Biochemical Society Transactions is the reviews journal of the Biochemical Society. Publishing concise reviews written by experts in the field, providing a timely snapshot of the latest developments across all areas of the molecular and cellular biosciences.
Elevating our authors’ ideas and expertise, each review includes a perspectives section where authors offer comment on the latest advances, a glimpse of future challenges and highlighting the importance of associated research areas in far broader contexts.