PgmNr Z625: Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis.

Authors:
A. Cox 1 ; A. Kim 1 ; D. Saunders 1 ; A. Tsomides 1 ; K. Hwang 1 ; K. Evason 2 ; J. Heidel 3 ; K. Brown 4 ; M. Yuan 4 ; E. Lien 4 ; B. Lee 1,5 ; S. Nissim 1 ; B. Dickinson 6 ; S. Chhangawala 7 ; C. Chang 8,9 ; J. Asara 4 ; Y. Houvras 7 ; V. Gladyshev 1,12 ; W. Goessling 1,10,11,12


Institutes
1) Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 2) University of Utah, Salt Lake City, UT; 3) Oregon State University, Corvallis, OR; 4) Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 5) Korea University, Seoul, South Korea; 6) University of Chicago, Chicago, IL; 7) Weill Cornell Medical College and New York Presbyterian Hospital, NY; 8) Howard Hughes Medical Institute; 9) University of California, Berkeley, Berkeley, CA; 10) Harvard Stem Cell Institute, Cambridge, MA; 11) Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 12) Broad Institute of MIT and Harvard, Cambridge, MA.


Abstract:

Selenium is an essential micronutrient, known for its cancer prevention properties, that is incorporated into a class of selenocysteine-containing proteins (selenoproteins). The human genome encodes 25 selenoproteins which play diverse roles in redox homeostasis, thyroid hormone metabolism, endoplasmic reticulum function and selenium transport. Selenoprotein H (seph) is a recently identified nucleolar oxidoreductase with DNA-binding properties whose function is not well understood. Here, we discover that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impaired redox balance by reducing the levels of ascorbate and methionine, whilst increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induced an inflammatory response and activated the p53 pathway. Consequently, loss of seph rendered 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, these studies 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.



ZFIN Genetics Index
1. seph
2. tp53