Bhatt, SchwetaGupta, ManojKhamaisi, MogherMartinez, RachaelGritsenko, MAWagner, Bridget K.Guye, PatrickBusskamp, VolkerShirakawa, JunWu, GongxiongLiew, CWClauss, ThereseValdez, IvanEl Ouaamari, AbdelfattahDirice, ErcumentTakatani, TomozumiKeenan, Hillary A.Smith, RDChurch, GeorgeWeiss, RonWagers, AmyQian, Wei-JunKing, GeorgeKulkarni, Rohit2022-07-212015-08-04Bhatt, Schweta, Manoj Gupta, Mogher Khamaisi, Rachael Martinez, MA Gritsenko, Bridget K. Wagner, Patrick Guye et al. "Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes." Cell Metabolism 22, no. 2 (2015): 239-252. DOI: 10.1016/j.cmet.2015.07.0151550-41311932-7420https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372779The 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.en-USResearch Subject Categories::MEDICINE::Dermatology and venerology,clinical genetics, internal medicine::Internal medicine::DiabetologyJournal Article2017-08-0220152022-07-2110.1016/j.cmet.2015.07.015