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

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.
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ;  [1] ;  [3] ;  [1] ;  [4] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [4] ;  [8] ;  [6] more »;  [9] ;  [4] ;  [2] ;  [1] « less
  1. Harvard Medical School, Boston, MA (United States). Joslin Diabetes Center; Harvard Medical School, Boston, MA (United States). Brigham and Women's Hospital, Dept. of Medicine
  2. Harvard Medical School, Boston, MA (United States). Brigham and Women's Hospital, Dept. of Medicine; Harvard Medical School, Boston, MA (United States). Joslin Diabetes Center
  3. Harvard Medical School, Boston, MA (United States). Joslin Diabetes Center
  4. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division
  5. Broad Institute of Massachusetts Inst. of Technology and Harvard, Cambridge, MA (United States)
  6. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Dept. of Biological Engineering
  7. Harvard Medical School, Boston, MA (United States). Dept. of Genetics; Technical Univ., Dresden (Germany). Center for Regenerative Therapies
  8. Harvard Medical School, Boston, MA (United States). Dept. of Genetics
  9. Harvard Medical School, Boston, MA (United States). Joslin Diabetes Center; Harvard Univ., Cambridge, MA (United States). Howard Hughes Medical Inst., Dept. of Stem Cell and Regenerative Biology, and Harvard Stem Cell Inst.
Publication Date:
Report Number(s):
PNNL-SA-113658
Journal ID: ISSN 1550-4131; 48705; 400412000
Grant/Contract Number:
AC05-76RL01830; RO1 DK67536; RO1 103215; UC4 DK104167-01; DP2OD006668; DP3 DK094333-01; P41 GM103493; 10-2012-240
Type:
Published Article
Journal Name:
Cell Metabolism
Additional Journal Information:
Journal Volume: 22; Journal Issue: 2; Journal ID: ISSN 1550-4131
Publisher:
Cell Press
Research Org:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Environmental Molecular Sciences Laboratory
OSTI Identifier:
1282426
Alternate Identifier(s):
OSTI ID: 1229927; OSTI ID: 1252578