Title

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

Authors

Jian Chen, University of Texas MD Anderson Cancer Center
Vivek Shukla, University of Texas MD Anderson Cancer Center
Patrizia Farci, National Institute of Allergy and Infectious Diseases (NIAID)
Jaclyn Andricovich, The George Washington University
Wilma Jogunoori, Washington DC VA Medical Center
Lawrence N. Kwong, University of Texas MD Anderson Cancer Center
Lior H. Katz, University of Texas MD Anderson Cancer Center
Kirti Shetty, Johns Hopkins School of Medicine
Asif Rashid, University of Texas MD Anderson Cancer Center
Xiaoping Su, University of Texas MD Anderson Cancer Center
Jon White, Washington DC VA Medical Center
Lei Li, University of Texas MD Anderson Cancer Center
Alan Yaoqi Wang, University of Texas MD Anderson Cancer Center
Boris Blechacz, University of Texas MD Anderson Cancer Center
Gottumukkala S. Raju, University of Texas MD Anderson Cancer Center
Marta Davila, University of Texas MD Anderson Cancer Center
Bao Ngoc Nguyen, The George Washington University
John R. Stroehlein, University of Texas MD Anderson Cancer Center
Junjie Chen, University of Texas MD Anderson Cancer Center
Sang Soo Kim, National Cancer Center, Gyeonggi
Heather Levin, The George Washington University
Keigo Machida, University of Southern California
Hidekazu Tsukamoto, University of Southern California
Peter Michaely, UT Southwestern Medical Center
Alexandros Tzatsos, The George Washington University
Bibhuti Mishra, Washington DC VA Medical Center
Richard Amdur, The George Washington University
Lopa Mishra, Washington DC VA Medical Center

Document Type

Journal Article

Publication Date

2-1-2017

Journal

Hepatology

Volume

65

Issue

2

DOI

10.1002/hep.28927

Abstract

© 2016 by the American Association for the Study of Liver Diseases. 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).

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