Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes
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Weiss_Preserved DNA Damage Checkpoint.pdf
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Author(s)
Bhatt, Shweta
Gupta, Manoj K.
Khamaisi, Mogher
Martinez, Rachael
Gritsenko, Marina A.
Wagner, Bridget K.
Guye, Patrick
Busskamp, Volker
Shirakawa, Jun
Wu, Gongxiong
Date Issued
May 2015
Journal
Cell Metabolism
Publisher
Elsevier
Citation
Bhatt, Shweta et al. “Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes.” Cell Metabolism 22.2 (2015): 239–252.
Version
Author's final manuscript
Abstract
The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D(disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild
complications (Medalist −C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist −C. In silico
analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced
susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200-regulated DNA damage checkpoint
pathway as a potential therapeutic target for treating complications of diabetes
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.cmet.2015.07.015
