Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage

Stem Cell Reports
Timothy M ChlonSusanne I Wells

Abstract

Pluripotent 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.

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Citations

Jun 23, 2016·Radiation Research·Kalpana MujooTej K Pandita
Dec 9, 2016·Expert Review of Hematology·Christen L EbensJohn E Wagner
Sep 24, 2016·Balsaeng'gwa saengsig·Jae-Young LeeKyung-Soon Park
Jul 25, 2017·BioResearch Open Access·Takaharu NegoroAkifumi Matsuyama
Aug 18, 2018·Human Gene Therapy·Paula RíoJuan A Bueren
Nov 25, 2020·Cell Stem Cell·Sonya Ruiz-TorresSusanne I Wells
Apr 7, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Chinnadurai ManiKomaraiah Palle

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Methods Mentioned

BETA
biopsies
biopsy
transfection
Assay

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