Loss of the transforming growth factor‐β effector β2‐Spectrin promotes genomic instability
| Autor: | Asif Rashid, Peter Michaely, Heather Levin, Sang Soo Kim, Kirti Shetty, Lior H. Katz, Richard Amdur, Jian Chen, Hidekazu Tsukamoto, Lei Li, Vivek Shukla, Xiaoping Su, Alan Yaoqi Wang, Junjie Chen, Keigo Machida, Gottumukkala S. Raju, Patrizia Farci, Alexandros Tzatsos, John R. Stroehlein, Lawrence N. Kwong, Jon White, Bao Ngoc Nguyen, Wilma Jogunoori, Boris Blechacz, Marta L. Davila, Bibhuti Mishra, Lopa Mishra, Jaclyn Andricovich |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Genome instability congenital hereditary and neonatal diseases and abnormalities Hepatology DNA repair DNA damage nutritional and metabolic diseases DNA Repair Pathway Biology medicine.disease Molecular biology Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Real-time polymerase chain reaction chemistry Fanconi anemia hemic and lymphatic diseases 030220 oncology & carcinogenesis FANCD2 medicine DNA |
| Zdroj: | Hepatology. 65:678-693 |
| ISSN: | 1527-3350 0270-9139 |
| Popis: | Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury, and promotes the development of cancer. We report here a major role for the TGF-β/Smad3 adaptor β2-Spectrin (β2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. β2SP supports DNA repair through β2SP-dependent activation of Fancd2, a core component of the Fanconi anemia complex. Loss of β2SP leads to decreased Fancd2 levels and sensitizes β2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both Aldh2 and Fancd2, and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA cross-linking agents, and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/TGF-β stimulation is regulated by the β2SP/Smad3 complex. Thus, dysfunctional TGF-β/β2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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