کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2093287 1081951 2016 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیوتکنولوژی یا زیست‌فناوری
پیش نمایش صفحه اول مقاله
Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage
چکیده انگلیسی


• Self-renewal but not pluripotency of iPSCs depends on FA pathway function
• Hyperactive CHK1 limits self-renewal in a conditional FA-deficient iPSC model
• CHK1 inhibition rescues long-term growth of FA-deficient iPSCs

SummaryPluripotent stem cells (PSCs) maintain a low mutation frequency compared with somatic cell types at least in part by preferentially utilizing error-free homologous recombination (HR) for DNA repair. Many endogenous metabolites cause DNA interstrand crosslinks, which are repaired by the Fanconi anemia (FA) pathway using HR. To determine the effect of failed repair of endogenous DNA lesions on PSC biology, we generated iPSCs harboring a conditional FA pathway. Upon FA pathway loss, iPSCs maintained pluripotency but underwent profound G2 arrest and apoptosis, whereas parental fibroblasts grew normally. Mechanistic studies revealed that G2-phase FA-deficient iPSCs possess large γH2AX-RAD51 foci indicative of accrued DNA damage, which correlated with activated DNA-damage signaling through CHK1. CHK1 inhibition specifically rescued the growth of FA-deficient iPSCs for prolonged culture periods, surprisingly without stimulating excessive karyotypic abnormalities. These studies reveal that PSCs possess hyperactive CHK1 signaling that restricts their self-renewal in the absence of error-free DNA repair.

Graphical AbstractFigure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 6, Issue 1, 12 January 2016, Pages 44–54
نویسندگان
, , , , , , , , , ,