Nuclear selenoproteins and genome maintenance

Abstract

Selenium is an essential metalloid required for the expression of selenoproteins. While cells are constantly challenged by clastogens of endogenous and exogenous origins, genome integrity is maintained by direct repair of DNA damage, redox balance, and epigenetic regulation. To date, only five selenoproteins are experimentally demonstrated to reside in nucleus, exclusively or partially, including selenoprotein H, methionine-R-sulfoxide reductase 1, glutathione peroxidase-4, thioredoxin reductase-1, and thioredoxin glutathione reductase. All these five selenoproteins have demonstrated or potential roles in redox regulation and genome maintenance. Selenoprotein H is known to transactivate the expression of a couple of genes against oxidative stress. The thioredoxin reductase-1b isoform delivers estrogen receptor-a and -b to the nucleus. Nuclear glutathione peroxidase-4 epigenetically and globally inhibits gene expression through the maintenance of chromatin compactness in testes. Continued studies on how these and additional nuclear selenoproteins regulate genome stability will have profound impact on advancing our understanding in selenium regulation of optimal health. V C 2015 IUBMB Life, 68(1): [5][6][7][8][9][10][11][12] 2016

GPX1 Localizes to the Nucleus in Prostate Epithelium and its Levels are not Associated with Prostate Cancer Recurrence

“…How GPX1 enters the nucleus of prostate epithelial cells is unknown. A search for nuclear localization sequences (NLS) among the 25 human selenoproteins using cNLS Mapper, a program that is specifically designed to recognize mono- and bi-partite NLS, revealed possible NLS in 15 selenoproteins, including GPX2 and GPX4, but not GPX1 [ 32 ]. As a tetramer of molecular weight of approximately 100 kDa, GPX1 is too large to freely diffuse into the nucleus [ 33 ], raising the possibility that GPX1 enters the nucleus as a monomer, or by a yet-to-be-resolved transport mechanism.…”

Selenium as a Bioactive Micronutrient in the Human Diet and Its Cancer Chemopreventive Activity

“…In 2017, Yang et al [ 97 ] proved that Trx regulates the concentration of selenoproteins (including Gpx1–4 and TrxR) in chickens by affecting the gene expression of these proteins. In turn, the activity of TrxR affects the functioning of Trx [ 98 ], which indicates that three components are responsible for regulating the expression of selenoproteins: Se, TrxR, and thioredoxin [ 99 , 100 ]. As strong electrons donors, thioredoxins are reducers for enzymes, e.g., ribonucleotide reductase during the synthesis of deoxyribonucleotides or thioredoxin peroxidase, which is part of the antioxidant system [ 101 ].…”

Selenoprotein O deficiencies suppress chondrogenic differentiation of ATDC5 cells

“…For example, GPx are capable of reducing various peroxides, TrxR maintain the reduction state of thioredoxin, DIO are involved in the activation or deactivation of thyroid hormones, and selenoprotein R deoxygenize methionine sulfoxide residues in proteins (Brigelius-Floh e and Maiorino, 2013;Boschi-Muller and Branlant, 2014;Lu and Holmgren, 2014;Schweizer and Steegborn, 2015). Whereas selenoprotein P is essential for Se homeostasis and distribution and SPS2 is responsible for selenocysteine synthesis (Hoffmann et al, 2007;Xu et al, 2007), other selenoproteins such as selenoprotein H, M, N, S, T, and W are less characterized, although many of these proteins are also likely involved in oxidoreductive reaction (Sengupta et al, 2009;Reeves et al, 2010;Castets et al, 2012;Raman et al, 2013;Speckmann et al, 2014;Zhang et al, 2016). Some selenoproteins are essential for cell proliferation, differentiation, and cell death of various cell types, while others such as TrxR2 and GPx4 are indispensible for embryogenesis and tissue homeostasis postnatal (Labunskyy et al, 2014).…”