Loss of the Transforming Growth Factor-β Effector β2-Spectrin Promotes Genomic Instability

被引：32

作者：

Chen, Jian ^{[1
]}

Shukla, Vivek ^{[1
,2
]}

Farci, Patrizia ^{[3
]}

Andricovich, Jaclyn ^{[4
]}

Jogunoori, Wilma ^{[5
]}

Kwong, Lawrence N. ^{[6
]}

Katz, Lior H. ^{[1
,7
]}

Shetty, Kirti ^{[8
]}

Rashid, Asif ^{[9
]}

Su, Xiaoping ^{[10
]}

White, Jon ^{[5
]}

Li, Lei ^{[11
]}

Wang, Alan Yaoqi ^{[12
]}

Blechacz, Boris ^{[1
]}

Raju, Gottumukkala S. ^{[1
]}

Davila, Marta ^{[1
]}

Nguyen, Bao-Ngoc

Stroehlein, John R. ^{[1
]}

Chen, Junjie ^{[11
]}

Kim, Sang Soo ^{[14
]}

Levin, Heather ^{[13
]}

Machida, Keigo ^{[15
,16
]}

Tsukamoto, Hidekazu ^{[15
,17
,18
]}

Michaely, Peter ^{[19
]}

Tzatsos, Alexandros ^{[4
]}

Mishra, Bibhuti ^{[5
,13
,20
]}

Amdur, Richard ^{[13
,20
]}

Mishra, Lopa ^{[5
,13
,20
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA

[2] Natl Canc Inst, Thorac & Gastrointestinal Oncol Branch, Thorac Oncol Sect, Bethesda, MD USA

[3] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Infect Dis Lab, Hepat Pathogenesis Sect, Bethesda, MD USA

[4] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC USA

[5] Vet Affairs Med Ctr, Inst Clin Res, Washington, DC USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA

[7] Sheba Med Ctr, Dept Gastroenterol, Tel Hashomer, Israel

[8] Johns Hopkins Univ, Sch Med, Div Gastroenterol & Hepatol, Baltimore, MD USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[13] George Washington Univ, Dept Surg, Washington, DC USA

[14] Natl Canc Ctr, Radiat Med Branch, Goyang, South Korea

[15] Southern Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA USA

[16] Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA USA

[17] Univ Southern Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA USA

[18] Greater Angeles Healthcare Syst, Dept Vet Affairs, Los Angeles, CA USA

[19] Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA

[20] George Washington Univ, Ctr Translat Med, Dept Surg, Washington, DC USA

来源：

HEPATOLOGY | 2017年 / 65卷 / 02期

关键词：

TGF-BETA; DNA-DAMAGE; STEM-CELLS; SPECTRIN; ANEMIA; REPAIR; CANCER; MICE; SUSCEPTIBILITY; INACTIVATION;

D O I：

10.1002/hep.28927

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 b/ mothers against decapentaplegic homolog 3 adaptor beta 2-Spectrin (beta 2SP, gene Sptbn1) in maintaining genomic stability following alcohol- induced DNA damage. b2SP supports DNA repair through beta 2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of beta 2SP leads to decreased Fancd2 levels and sensitizes beta 2SP 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 beta stimulation is regulated by the beta 2SP/ mothers against decapentaplegic homolog 3 complex. Conclusion: Dysfunctional transforming growth factor beta/beta 2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway.

引用

页码：678 / 693

页数：16

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