title: Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability.
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.
  
  
  
  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).
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.|Thoracic Oncology Section, Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Vivek
authors.initials: V
authors.lastname: Shukla
authors.affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Farci
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Andricovich
authors.affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC.
authors.forename: Wilma
authors.initials: W
authors.lastname: Jogunoori
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Lior H
authors.initials: LH
authors.lastname: Katz
authors.affiliation: Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Kirti
authors.initials: K
authors.lastname: Shetty
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC.
authors.forename: Jon
authors.initials: J
authors.lastname: White
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Alan Yaoqi
authors.initials: AY
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Boris
authors.initials: B
authors.lastname: Blechacz
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Gottumukkala S
authors.initials: GS
authors.lastname: Raju
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Marta
authors.initials: M
authors.lastname: Davila
authors.affiliation: Department of Surgery, George Washington University, Washington, DC.
authors.forename: Bao-Ngoc
authors.initials: BN
authors.lastname: Nguyen
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: John R
authors.initials: JR
authors.lastname: Stroehlein
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.affiliation: National Cancer Center, Radiation Medicine Branch, Goyang, Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Department of Surgery, George Washington University, Washington, DC.
authors.forename: Heather
authors.initials: H
authors.lastname: Levin
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, University of Southern California, Los Angeles, CA.|Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, University of Southern California, Los Angeles, CA.|Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA.|Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, CA.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Peter
authors.initials: P
authors.lastname: Michaely
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Tzatsos
authors.affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC.|Department of Surgery, George Washington University, Washington, DC.|Center for Translational Medicine, Department of Surgery, George Washington University.
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Mishra
authors.affiliation: Department of Surgery, George Washington University, Washington, DC.|Center for Translational Medicine, Department of Surgery, George Washington University.
authors.forename: Richard
authors.initials: R
authors.lastname: Amdur
authors.affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC.|Department of Surgery, George Washington University, Washington, DC.|Center for Translational Medicine, Department of Surgery, George Washington University.
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000235:genetics / Q000473:pathology; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011270:Pregnancy, Animal; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D013049:Spectrin / Q000235:genetics*; D053781:Transforming Growth Factor beta2 / Q000235:genetics*
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D053781:Transforming Growth Factor beta2; D013049:Spectrin; D000431:Ethanol