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

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

Authors:
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Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1282426
Alternate Identifier(s):
OSTI ID: 1229927; OSTI ID: 1252578
Report Number(s):
PNNL-SA-113658
Journal ID: ISSN 1550-4131; S1550413115003447; PII: S1550413115003447
Grant/Contract Number:  
AC05-76RL01830; RO1 DK67536; RO1 103215; UC4 DK104167-01; DP2OD006668; DP3 DK094333-01; P41 GM103493; 10-2012-240
Resource Type:
Published Article
Journal Name:
Cell Metabolism
Additional Journal Information:
Journal Name: Cell Metabolism Journal Volume: 22 Journal Issue: 2; Journal ID: ISSN 1550-4131
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Environmental Molecular Sciences Laboratory

Citation Formats

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., and Kulkarni, Rohit N. Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes. United States: N. p., 2015. Web. doi:10.1016/j.cmet.2015.07.015.
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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. Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes. United States. https://doi.org/10.1016/j.cmet.2015.07.015
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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., and Kulkarni, Rohit N. Sat . "Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes". United States. https://doi.org/10.1016/j.cmet.2015.07.015.
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@article{osti_1282426,
title = {Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes},
author = {Bhatt, Shweta and Gupta, Manoj K. and Khamaisi, Mogher and Martinez, Rachael and Gritsenko, Marina A. and Wagner, Bridget K. and Guye, Patrick and Busskamp, Volker and Shirakawa, Jun and Wu, Gongxiong and Liew, Chong Wee and Clauss, Therese R. and Valdez, Ivan and El Ouaamari, Abdelfattah and Dirice, Ercument and Takatani, Tomozumi and Keenan, Hillary A. and Smith, Richard D. and Church, George and Weiss, Ron and Wagers, Amy J. and Qian, Wei-Jun and King, George L. and Kulkarni, Rohit N.},
abstractNote = {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.},
doi = {10.1016/j.cmet.2015.07.015},
journal = {Cell Metabolism},
number = 2,
volume = 22,
place = {United States},
year = {Sat Aug 01 00:00:00 EDT 2015},
month = {Sat Aug 01 00:00:00 EDT 2015}
}
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https://doi.org/10.1016/j.cmet.2015.07.015
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Works referencing / citing this record:

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The current state of the art of quantitative phosphoproteomics and its applications to diabetes research
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  • Chan, Chi Yuet X’avia; Gritsenko, Marina A.; Smith, Richard D.
  • Expert Review of Proteomics, Vol. 13, Issue 4
  • DOI: 10.1586/14789450.2016.1164604
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