Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo
作者： Yang Yang , Jonathan C. Poe , Lisong Yang , Andrew Fedoriw , Siddhi Desai
DOI: 10.1093/NAR/GKW072
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摘要: In cultured cancer cells the E3 ubiquitin ligase Rad18 activates Trans-Lesion Synthesis (TLS) and Fanconi Anemia (FA) pathway. However, physiological roles of in DNA damage tolerance carcinogenesis are unknown were investigated here. Primary hematopoietic stem progenitor (HSPC) co-expressed RAD18 FANCD2 proteins, potentially consistent with a role for FA pathway function during hematopoiesis. defects typically associated fanc-deficiency (decreased HSPC numbers, reduced engraftment potential HSPC, Mitomycin C (MMC) -sensitive hematopoiesis), absent Rad18(-/-) mice. Moreover, primary mouse embryonic fibroblasts (MEF) retained robust Fancd2 mono-ubiquitination following MMC treatment. Therefore, is dispensable activation untransformed pathways separable cells. contrast responses to crosslinking agents, sensitive vivo treatment myelosuppressive agent 7,12 Dimethylbenz[a]anthracene (DMBA). Rad18-deficient aberrantly accumulated markers after DMBA led increased incidence B cell malignancy These results identify novel functions provide first demonstration that confers tumor-suppression setting.
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