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Hepatology. 2017 Feb;65(2):678-693. doi: 10.1002/hep.28927. Epub 2016 Dec 24.

Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability.

Author information

  • 1Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.
  • 2Thoracic Oncology Section, Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD.
  • 3Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 4Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC.
  • 5Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC.
  • 6Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • 7Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Israel.
  • 8Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD.
  • 9Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • 10Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • 11Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • 12Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • 13Department of Surgery, George Washington University, Washington, DC.
  • 14National Cancer Center, Radiation Medicine Branch, Goyang, Korea.
  • 15Southern California Research Center for ALPD and Cirrhosis, University of Southern California, Los Angeles, CA.
  • 16Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
  • 17Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
  • 18Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, CA.
  • 19Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX.
  • 20Center for Translational Medicine, Department of Surgery, George Washington University.

Abstract

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 transforming growth factor β/mothers against decapentaplegic homolog 3 adaptor β2-Spectrin (β2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. β2SP supports DNA repair through β2SP-dependent activation of Fanconi anemia complementation group D2 (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 aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor β stimulation is regulated by the β2SP/mothers against decapentaplegic homolog 3 complex.

CONCLUSION:

Dysfunctional transforming growth factor β/β2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).

PMID:
28114741
DOI:
10.1002/hep.28927
[PubMed - in process]
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