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Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):E5562-71. doi: 10.1073/pnas.1600204113. Epub 2016 Sep 1.

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis.

Author information

1
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
2
University of Utah, Salt Lake City, UT 84112;
3
Oregon State University, Corvallis, OR 97331;
4
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
5
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Korea University, 02841 Seoul, Republic of Korea;
6
University of Chicago, Chicago, IL 60637;
7
Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065;
8
Howard Hughes Medical Institute, Bethesda, MD 20815; University of California, Berkeley, CA 20815;
9
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142;
10
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142; Harvard Stem Cell Institute, Cambridge, MA 02138; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 wgoessling@partners.org.

Abstract

Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.

KEYWORDS:

endoderm development; liver cancer; p53; selenium; selenoproteins

PMID:
27588899
PMCID:
PMC5035897
DOI:
10.1073/pnas.1600204113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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