Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo.
Abstract
In cultured cancer cells the E3 ubiquitin ligase Rad18 activates Trans-Lesion Synthesis
(TLS) and the Fanconi Anemia (FA) pathway. However, physiological roles of Rad18 in
DNA damage tolerance and carcinogenesis are unknown and were investigated here. Primary
hematopoietic stem and progenitor cells (HSPC) co-expressed RAD18 and FANCD2 proteins,
potentially consistent with a role for Rad18 in FA pathway function during hematopoiesis.
However, hematopoietic defects typically associated with fanc-deficiency (decreased
HSPC numbers, reduced engraftment potential of HSPC, and Mitomycin C (MMC) -sensitive
hematopoiesis), were absent in Rad18(-/-) mice. Moreover, primary Rad18(-/-) mouse
embryonic fibroblasts (MEF) retained robust Fancd2 mono-ubiquitination following MMC
treatment. Therefore, Rad18 is dispensable for FA pathway activation in untransformed
cells and the Rad18 and FA pathways are separable in hematopoietic cells. In contrast
with responses to crosslinking agents, Rad18(-/-) HSPC were sensitive to in vivo treatment
with the myelosuppressive agent 7,12 Dimethylbenz[a]anthracene (DMBA). Rad18-deficient
fibroblasts aberrantly accumulated DNA damage markers after DMBA treatment. Moreover,
in vivo DMBA treatment led to increased incidence of B cell malignancy in Rad18(-/-)
mice. These results identify novel hematopoietic functions for Rad18 and provide the
first demonstration that Rad18 confers DNA damage tolerance and tumor-suppression
in a physiological setting.
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https://hdl.handle.net/10161/12561Published Version (Please cite this version)
10.1093/nar/gkw072Publication Info
Yang, Yang; Poe, Jonathan C; Yang, Lisong; Fedoriw, Andrew; Desai, Siddhi; Magnuson,
Terry; ... Vaziri, Cyrus (2016). Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of
the Fanconi Anemia pathway in vivo. Nucleic Acids Res, 44(9). pp. 4174-4188. 10.1093/nar/gkw072. Retrieved from https://hdl.handle.net/10161/12561.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Zhiguo Li
Associate Professor of Biostatistics & Bioinformatics
survival analysis, dynamic treatment regimes, clinical trials
Stefanie Sarantopoulos
Professor of Medicine
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