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Article ; Online: Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6.

Santesmasses, Didac / Gladyshev, Vadim N

2022 Volume 12, Issue 8

Abstract: The human genome has 25 genes coding for selenocysteine (Sec)-containing proteins, whose synthesis is supported by specialized Sec machinery proteins. Here, we carried out an analysis of the co-essentiality network to identify functional partners of ... ...

Abstract	The human genome has 25 genes coding for selenocysteine (Sec)-containing proteins, whose synthesis is supported by specialized Sec machinery proteins. Here, we carried out an analysis of the co-essentiality network to identify functional partners of selenoproteins and Sec machinery. One outstanding cluster included all seven known Sec machinery proteins and two critical selenoproteins, GPX4 and TXNRD1. Additionally, these nine genes were further positively associated with PRDX6 and negatively with SCD, linking the latter two genes to the essential role of selenium. We analyzed the essentiality scores of gene knockouts in this cluster across one thousand cancer cell lines and found that Sec metabolism genes are strongly selective for a subset of primary tissues, suggesting that certain cancer cell lineages are particularly dependent on selenium. A separate outstanding cluster included selenophosphate synthetase SEPHS1, which was linked to a group of transcription factors, whereas the remaining selenoproteins were linked neither to these clusters nor among themselves. The data suggest that key components of Sec machinery have already been identified and that their primary role is to support the functions of GPX4 and TXNRD1, with further functional links to PRDX6 and SCD.
MeSH term(s)	Cell Line ; Genome, Human ; Humans ; Peroxiredoxin VI/genetics ; Peroxiredoxin VI/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Selenium/metabolism ; Selenocysteine/genetics ; Selenocysteine/metabolism ; Selenoproteins/genetics ; Selenoproteins/metabolism ; Stearoyl-CoA Desaturase/metabolism ; Thioredoxin Reductase 1/genetics ; Thioredoxin Reductase 1/metabolism
Chemical Substances	Selenoproteins ; Selenocysteine (0CH9049VIS) ; Phospholipid Hydroperoxide Glutathione Peroxidase (EC 1.11.1.12) ; PRDX6 protein, human (EC 1.11.1.15) ; Peroxiredoxin VI (EC 1.11.1.15) ; SCD1 protein, human (EC 1.14.19.1) ; Stearoyl-CoA Desaturase (EC 1.14.19.1) ; TXNRD1 protein, human (EC 1.8.1.9) ; Thioredoxin Reductase 1 (EC 1.8.1.9) ; Selenium (H6241UJ22B)
Language	English
Publishing date	2022-07-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12081049
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Pathogenic Variants in Selenoproteins and Selenocysteine Biosynthesis Machinery.

Santesmasses, Didac / Gladyshev, Vadim N

International journal of molecular sciences

2021 Volume 22, Issue 21

Abstract: Selenium is incorporated into selenoproteins as the 21st amino acid selenocysteine (Sec). There are 25 selenoproteins encoded in the human genome, and their synthesis requires a dedicated machinery. Most selenoproteins are oxidoreductases with important ... ...

Abstract	Selenium is incorporated into selenoproteins as the 21st amino acid selenocysteine (Sec). There are 25 selenoproteins encoded in the human genome, and their synthesis requires a dedicated machinery. Most selenoproteins are oxidoreductases with important functions in human health. A number of disorders have been associated with deficiency of selenoproteins, caused by mutations in selenoprotein genes or Sec machinery genes. We discuss mutations that are known to cause disease in humans and report their allele frequencies in the general population. The occurrence of protein-truncating variants in the same genes is also presented. We provide an overview of pathogenic variants in selenoproteins genes from a population genomics perspective.
MeSH term(s)	Alleles ; Animals ; Genetic Variation/genetics ; Genome, Human/genetics ; Humans ; Selenium/metabolism ; Selenocysteine/genetics ; Selenoproteins/genetics
Chemical Substances	Selenoproteins ; Selenocysteine (0CH9049VIS) ; Selenium (H6241UJ22B)
Language	English
Publishing date	2021-10-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222111593
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Article ; Online: Pathogenic Variants in Selenoproteins and Selenocysteine Biosynthesis Machinery

Didac Santesmasses / Vadim N. Gladyshev

International Journal of Molecular Sciences, Vol 22, Iss 11593, p

2021 Volume 11593

Abstract	Selenium is incorporated into selenoproteins as the 21st amino acid selenocysteine (Sec). There are 25 selenoproteins encoded in the human genome, and their synthesis requires a dedicated machinery. Most selenoproteins are oxidoreductases with important functions in human health. A number of disorders have been associated with deficiency of selenoproteins, caused by mutations in selenoprotein genes or Sec machinery genes. We discuss mutations that are known to cause disease in humans and report their allele frequencies in the general population. The occurrence of protein-truncating variants in the same genes is also presented. We provide an overview of pathogenic variants in selenoproteins genes from a population genomics perspective.
Keywords	selenium ; selenoprotein ; selenocysteine ; genetic variance ; human disease ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Bioinformatics of Selenoproteins.

Santesmasses, Didac / Mariotti, Marco / Gladyshev, Vadim N

Antioxidants & redox signaling

2020 Volume 33, Issue 7, Page(s) 525–536

Abstract: Significance: ...

Abstract	Significance:
MeSH term(s)	Animals ; Computational Biology/methods ; Humans ; Protein Biosynthesis ; Research ; Selenocysteine/metabolism ; Selenoproteins/genetics ; Selenoproteins/metabolism
Chemical Substances	Selenoproteins ; Selenocysteine (0CH9049VIS)
Language	English
Publishing date	2020-04-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2020.8044
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Article ; Online: COVID-19 mortality rate in children is U-shaped.

Khera, Nina / Santesmasses, Didac / Kerepesi, Csaba / Gladyshev, Vadim N

Aging

2021 Volume 13, Issue 16, Page(s) 19954–19962

Abstract: Children are known to be better protected from COVID-19 than adults, but their susceptibility patterns and the risk relative to other diseases are insufficiently defined. Here, we found that the COVID-19 mortality rate is U-shaped in childhood: it ... ...

Abstract	Children are known to be better protected from COVID-19 than adults, but their susceptibility patterns and the risk relative to other diseases are insufficiently defined. Here, we found that the COVID-19 mortality rate is U-shaped in childhood: it initially decreases, reaching the minimum at the ages 3-10 years, and then increases throughout life. All-cause mortality and mortality from other diseases, such as pneumonia and influenza, show a similar pattern; however, childhood mortality rates from COVID-19 are considerably lower than from other diseases, with the best relative protection achieved at the youngest ages. Consistent with this, the fraction of COVID-19 deaths among all deaths increases as a function of age throughout childhood and the entire life. We discuss implications of the elevated postnatal COVID-19 risk and lower childhood COVID-19 mortality compared to other diseases.
MeSH term(s)	Adolescent ; Adult ; Age Factors ; COVID-19/mortality ; Cause of Death ; Child ; Child, Preschool ; Humans ; Infant ; Middle Aged ; Survival Rate ; Young Adult
Language	English
Publishing date	2021-08-18
Publishing country	United States
Document type	Journal Article
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.203442
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Article ; Online: Historical Roles of Selenium and Selenoproteins in Health and Development

Petra A. Tsuji / Didac Santesmasses / Byeong J. Lee / Vadim N. Gladyshev / Dolph L. Hatfield

International Journal of Molecular Sciences, Vol 23, Iss 5, p

The Good, the Bad and the Ugly

2022 Volume 5

Abstract: Selenium is a fascinating element that has a long history, most of which documents it as a deleterious element to health. In more recent years, selenium has been found to be an essential element in the diet of humans, all other mammals, and many other ... ...

Abstract	Selenium is a fascinating element that has a long history, most of which documents it as a deleterious element to health. In more recent years, selenium has been found to be an essential element in the diet of humans, all other mammals, and many other life forms. It has many health benefits that include, for example, roles in preventing heart disease and certain forms of cancer, slowing AIDS progression in HIV patients, supporting male reproduction, inhibiting viral expression, and boosting the immune system, and it also plays essential roles in mammalian development. Elucidating the molecular biology of selenium over the past 40 years generated an entirely new field of science which encompassed the many novel features of selenium. These features were (1) how this element makes its way into protein as the 21st amino acid in the genetic code, selenocysteine (Sec); (2) the vast amount of machinery dedicated to synthesizing Sec uniquely on its tRNA; (3) the incorporation of Sec into protein; and (4) the roles of the resulting Sec-containing proteins (selenoproteins) in health and development. One of the research areas receiving the most attention regarding selenium in health has been its role in cancer prevention, but further research has also exposed the role of this element as a facilitator of various maladies, including cancer.
Keywords	cancer ; health ; mouse models ; selenium ; selenocysteine (Sec) ; tRNA[Ser] Sec ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	170
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Tolerance to Selenoprotein Loss Differs between Human and Mouse.

Santesmasses, Didac / Mariotti, Marco / Gladyshev, Vadim N

Molecular biology and evolution

2019 Volume 37, Issue 2, Page(s) 341–354

Abstract: Mouse has emerged as the most common model organism in biomedicine. Here, we analyzed the tolerance to the loss-of-function (LoF) of selenoprotein genes, estimated from mouse knockouts and the frequency of LoF variants in humans. We found not only a ... ...

Abstract	Mouse has emerged as the most common model organism in biomedicine. Here, we analyzed the tolerance to the loss-of-function (LoF) of selenoprotein genes, estimated from mouse knockouts and the frequency of LoF variants in humans. We found not only a general correspondence in tolerance (e.g., GPX1, GPX2) and intolerance (TXNRD1, SELENOT) to gene LoF between humans and mice but also important differences. Notably, humans are intolerant to the loss of iodothyronine deiodinases, whereas their deletion in mice leads to mild phenotypes, and this is consistent with phenotype differences in selenocysteine machinery loss between these species. In contrast, loss of TXNRD2 and GPX4 is lethal in mice but may be tolerated in humans. We further identified the first human SELENOP variants coding for proteins varying in selenocysteine content. Finally, our analyses suggested that premature termination codons in selenoprotein genes trigger nonsense-mediated decay, but do this inefficiently when UGA codon is gained. Overall, our study highlights differences in the physiological importance of selenoproteins between human and mouse.
MeSH term(s)	Animals ; Gene Knockout Techniques/methods ; Humans ; Loss of Function Mutation ; Mice ; Nonsense Mediated mRNA Decay ; Phenotype ; RNA, Messenger/chemistry ; Selenoproteins/chemistry ; Selenoproteins/genetics ; Species Specificity
Chemical Substances	RNA, Messenger ; Selenoproteins
Language	English
Publishing date	2019-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/msz218
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Zs.A 2137: Show issues

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Article ; Online: Historical Roles of Selenium and Selenoproteins in Health and Development: The Good, the Bad and the Ugly.

Tsuji, Petra A / Santesmasses, Didac / Lee, Byeong J / Gladyshev, Vadim N / Hatfield, Dolph L

International journal of molecular sciences

2021 Volume 23, Issue 1

Abstract	Selenium is a fascinating element that has a long history, most of which documents it as a deleterious element to health. In more recent years, selenium has been found to be an essential element in the diet of humans, all other mammals, and many other life forms. It has many health benefits that include, for example, roles in preventing heart disease and certain forms of cancer, slowing AIDS progression in HIV patients, supporting male reproduction, inhibiting viral expression, and boosting the immune system, and it also plays essential roles in mammalian development. Elucidating the molecular biology of selenium over the past 40 years generated an entirely new field of science which encompassed the many novel features of selenium. These features were (1) how this element makes its way into protein as the 21st amino acid in the genetic code, selenocysteine (Sec); (2) the vast amount of machinery dedicated to synthesizing Sec uniquely on its tRNA; (3) the incorporation of Sec into protein; and (4) the roles of the resulting Sec-containing proteins (selenoproteins) in health and development. One of the research areas receiving the most attention regarding selenium in health has been its role in cancer prevention, but further research has also exposed the role of this element as a facilitator of various maladies, including cancer.
MeSH term(s)	Animals ; Diet ; Genetic Code ; Health ; Humans ; RNA, Transfer, Amino Acid-Specific/metabolism ; Selenium/administration & dosage ; Selenocysteine/metabolism ; Selenoproteins/metabolism
Chemical Substances	RNA, Transfer, Amino Acid-Specific ; Selenoproteins ; tRNA, selenocysteine- ; Selenocysteine (0CH9049VIS) ; Selenium (H6241UJ22B)
Language	English
Publishing date	2021-12-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23010005
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Article ; Online: Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.

Fernando, Raquel / Shindyapina, Anastasia V / Ost, Mario / Santesmasses, Didac / Hu, Yan / Tyshkovskiy, Alexander / Yim, Sun Hee / Weiss, Jürgen / Gladyshev, Vadim N / Grune, Tilman / Castro, José Pedro

Communications biology

2023 Volume 6, Issue 1, Page(s) 1240

Abstract: Skeletal muscle aging is characterized by the loss of muscle mass, strength and function, mainly attributed to the atrophy of glycolytic fibers. Underlying mechanisms driving the skeletal muscle functional impairment are yet to be elucidated. To ... ...

Abstract	Skeletal muscle aging is characterized by the loss of muscle mass, strength and function, mainly attributed to the atrophy of glycolytic fibers. Underlying mechanisms driving the skeletal muscle functional impairment are yet to be elucidated. To unbiasedly uncover its molecular mechanisms, we recurred to gene expression and metabolite profiling in a glycolytic muscle, Extensor digitorum longus (EDL), from young and aged C57BL/6JRj mice. Employing multi-omics approaches we found that the main age-related changes are connected to mitochondria, exhibiting a downregulation in mitochondrial processes. Consistent is the altered mitochondrial morphology. We further compared our mouse EDL aging signature with human data from the GTEx database, reinforcing the idea that our model may recapitulate muscle loss in humans. We are able to show that age-related mitochondrial downregulation is likely to be detrimental, as gene expression signatures from commonly used lifespan extending interventions displayed the opposite direction compared to our EDL aging signature.
MeSH term(s)	Animals ; Humans ; Mice ; Aging/genetics ; Down-Regulation ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism
Language	English
Publishing date	2023-12-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-05595-3
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Article ; Online: Selenoprofiles: A Computational Pipeline for Annotation of Selenoproteins.

Santesmasses, Didac / Mariotti, Marco / Guigó, Roderic

Methods in molecular biology (Clifton, N.J.)

2017 Volume 1661, Page(s) 17–28

Abstract: Selenoproteins contain selenocysteine (Sec or U), the 21st amino acid, inserted in response to an in-frame UGA codon. UGA normally terminates translation, but in selenoprotein mRNAs it is recoded to specify Sec insertion. For this reason, standard gene ... ...

Abstract	Selenoproteins contain selenocysteine (Sec or U), the 21st amino acid, inserted in response to an in-frame UGA codon. UGA normally terminates translation, but in selenoprotein mRNAs it is recoded to specify Sec insertion. For this reason, standard gene prediction programs fail to predict Sec codons, and selenoproteins are usually misannotated in protein databases and genome projects. Selenoprofiles is a computational pipeline able to correctly annotate selenoprotein genes in genomic sequences. This program uses a SECIS-independent approach, based on homology searches, and employs curated built-in profile alignments for all known selenoprotein families. Selenoprofiles constitutes the most accurate method for predicting selenoprotein genes belonging to known families.
MeSH term(s)	Codon, Terminator ; Computational Biology/methods ; Databases, Protein ; Genomics/methods ; Molecular Sequence Annotation ; Selenocysteine/chemistry ; Selenocysteine/genetics ; Selenoproteins/chemistry ; Selenoproteins/genetics ; Software ; User-Computer Interface ; Web Browser
Chemical Substances	Codon, Terminator ; Selenoproteins ; Selenocysteine (0CH9049VIS)
Language	English
Publishing date	2017-09-15
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7258-6_2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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