Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes

Journal Article · Sat Aug 01 00:00:00 EDT 2015 · Cell Metabolism

DOI:https://doi.org/10.1016/j.cmet.2015.07.015· OSTI ID:1282426

Bhatt, Shweta; Gupta, Manoj K.; Khamaisi, Mogher; Martinez, Rachael; Gritsenko, Marina A.; Wagner, Bridget K.; Guye, Patrick; Busskamp, Volker; Shirakawa, Jun; Wu, Gongxiong; Liew, Chong Wee; Clauss, Therese R.; Valdez, Ivan; El Ouaamari, Abdelfattah; Dirice, Ercument; Takatani, Tomozumi; Keenan, Hillary A.; Smith, Richard D.; Church, George; Weiss, Ron ; Wagers, Amy J.; Qian, Wei-Jun; King, George L.; Kulkarni, Rohit N.

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. Lastly, we propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)
• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER)
• Grant/Contract Number: AC05-76RL01830; RO1 DK67536; RO1 103215; UC4 DK104167-01; DP2OD006668; DP3 DK094333-01; P41 GM103493; 10-2012-240
• OSTI ID: 1282426
• Alternate ID(s): OSTI ID: 1229927; OSTI ID: 1252578
• Report Number(s): PNNL-SA-113658; S1550413115003447; PII: S1550413115003447
• Journal Information: Cell Metabolism, Journal Name: Cell Metabolism Vol. 22 Journal Issue: 2; ISSN 1550-4131
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Environmental Molecular Sciences Laboratory