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

Jian Chen, Vivek Shukla, Patrizia Farci, Jaclyn Andricovich, Wilma Jogunoori, Lawrence N. Kwong, Lior H. Katz, Kirti Shetty, Asif Rashid, Xiaoping Su, Jon White, Lei Li, Alan Yaoqi Wang, Boris Blechacz, Gottumukkala S. Raju, Marta Davila, Bao Ngoc Nguyen, John R. Stroehlein, Junjie Chen, Sang Soo Kim & 8 others Heather Levin, Keigo Machida, Hidekazu Tsukamoto, Peter Michaely, Alexandros Tzatsos, Bibhuti Mishra, Richard Amdur, Lopa Mishra

Research output: Contribution to journalArticle

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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).

Original languageEnglish (US)
Pages (from-to)678-693
Number of pages16
JournalHepatology
Volume65
Issue number2
DOIs
StatePublished - Feb 1 2017

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Fanconi Anemia
Spectrin
Genomic Instability
Transforming Growth Factors
DNA Damage
Smad Proteins
DNA Repair
Ethanol
Fetal Alcohol Spectrum Disorders
Aldehyde Dehydrogenase
Double-Stranded DNA Breaks
Acetaldehyde
Mutagens
Gastroenterology
Alcohols
Phenotype
Liver
DNA
Wounds and Injuries

ASJC Scopus subject areas

  • Hepatology

Cite this

Chen, J., Shukla, V., Farci, P., Andricovich, J., Jogunoori, W., Kwong, L. N., ... Mishra, L. (2017). Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability. Hepatology, 65(2), 678-693. https://doi.org/10.1002/hep.28927

Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability. / Chen, Jian; Shukla, Vivek; Farci, Patrizia; Andricovich, Jaclyn; Jogunoori, Wilma; Kwong, Lawrence N.; Katz, Lior H.; Shetty, Kirti; Rashid, Asif; Su, Xiaoping; White, Jon; Li, Lei; Wang, Alan Yaoqi; Blechacz, Boris; Raju, Gottumukkala S.; Davila, Marta; Nguyen, Bao Ngoc; Stroehlein, John R.; Chen, Junjie; Kim, Sang Soo; Levin, Heather; Machida, Keigo; Tsukamoto, Hidekazu; Michaely, Peter; Tzatsos, Alexandros; Mishra, Bibhuti; Amdur, Richard; Mishra, Lopa.

In: Hepatology, Vol. 65, No. 2, 01.02.2017, p. 678-693.

Research output: Contribution to journalArticle

Chen, J, Shukla, V, Farci, P, Andricovich, J, Jogunoori, W, Kwong, LN, Katz, LH, Shetty, K, Rashid, A, Su, X, White, J, Li, L, Wang, AY, Blechacz, B, Raju, GS, Davila, M, Nguyen, BN, Stroehlein, JR, Chen, J, Kim, SS, Levin, H, Machida, K, Tsukamoto, H, Michaely, P, Tzatsos, A, Mishra, B, Amdur, R & Mishra, L 2017, 'Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability', Hepatology, vol. 65, no. 2, pp. 678-693. https://doi.org/10.1002/hep.28927
Chen J, Shukla V, Farci P, Andricovich J, Jogunoori W, Kwong LN et al. Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability. Hepatology. 2017 Feb 1;65(2):678-693. https://doi.org/10.1002/hep.28927
Chen, Jian ; Shukla, Vivek ; Farci, Patrizia ; Andricovich, Jaclyn ; Jogunoori, Wilma ; Kwong, Lawrence N. ; Katz, Lior H. ; Shetty, Kirti ; Rashid, Asif ; Su, Xiaoping ; White, Jon ; Li, Lei ; Wang, Alan Yaoqi ; Blechacz, Boris ; Raju, Gottumukkala S. ; Davila, Marta ; Nguyen, Bao Ngoc ; Stroehlein, John R. ; Chen, Junjie ; Kim, Sang Soo ; Levin, Heather ; Machida, Keigo ; Tsukamoto, Hidekazu ; Michaely, Peter ; Tzatsos, Alexandros ; Mishra, Bibhuti ; Amdur, Richard ; Mishra, Lopa. / Loss of the transforming growth factor-β effector β2-Spectrin promotes genomic instability. In: Hepatology. 2017 ; Vol. 65, No. 2. pp. 678-693.
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AU - Shukla, Vivek

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AU - Jogunoori, Wilma

AU - Kwong, Lawrence N.

AU - Katz, Lior H.

AU - Shetty, Kirti

AU - Rashid, Asif

AU - Su, Xiaoping

AU - White, Jon

AU - Li, Lei

AU - Wang, Alan Yaoqi

AU - Blechacz, Boris

AU - Raju, Gottumukkala S.

AU - Davila, Marta

AU - Nguyen, Bao Ngoc

AU - Stroehlein, John R.

AU - Chen, Junjie

AU - Kim, Sang Soo

AU - Levin, Heather

AU - Machida, Keigo

AU - Tsukamoto, Hidekazu

AU - Michaely, Peter

AU - Tzatsos, Alexandros

AU - Mishra, Bibhuti

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N2 - 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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