Ski/Dach domain-containing protein 1 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the SKIDA1

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. It is also known as C10orf140 and DLN-1. It has orthologs in

vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

. It has two domains: the Ski/Sno/Dac domain and a

domain of unknown function A domain of unknown function (DUF) is a protein domain that has no characterised function. These families have been collected together in the Pfam database using the prefix DUF followed by a number, with examples being DUF2992 and DUF1220. As of 201 ...

, DUF4854. It is associated with multiple types of cancer, like

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

, and

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel mo ...

. It's predicted to be a nuclear protein. It may interact with PRC2.

Homologs

Orthologs

SKIDA1 has orthologs in vertebrate species. The species least related to humans with a SKIDA1 ortholog is the lancelet ''Branchiostoma belcheri''. The

clades A clade (), also known as a monophyletic group or natural group, is a group of organisms that are monophyletic – that is, composed of a common ancestor and all its lineal descendants – on a phylogenetic tree. Rather than the English term, t ...

amphibia Amphibians are four-limbed and ectothermic vertebrates of the class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terrestrial, fossorial, arbore ...

and chondrichthyes have at least two species with SKIDA1, but SKIDA1 is not found throughout the clades. No orthologs have been found in

lungfish Lungfish are freshwater vertebrates belonging to the order Dipnoi. Lungfish are best known for retaining ancestral characteristics within the Osteichthyes, including the ability to breathe air, and ancestral structures within Sarcopterygii, i ...

invertebrate Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...

species.

Paralogous Domains

SKIDA1 shares the Ski/Sno/Dac domain with Ski oncogene (Ski), Ski-like protein (Sno), and

dachshund The dachshund ( or ; German: "badger dog"), also known as the wiener dog, badger dog, and sausage dog, is a short-legged, long-bodied, hound-type dog breed. The dog may be smooth-haired, wire-haired, or long-haired, and comes in a variety of c ...

(Dac). It shares DUF4584 with Elongin BC Polycomb Repressive Complex 2 associated Protein (EPOP).

Structure

In humans, SKIDA1 is located on the reverse strand of chromosome 10 at locus 10p12.31. It contains five

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

Isoforms

There is not a consensus on whether humans have one or two SKIDA1

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

. NCBI Gene claims there is one, while UniProt claims there are two. It's possible isoform 2 is recorded in NCBI Gene as DLN-1 (accession BAE93016.1). Isoform 1 is 908 amino acids long, while isoform 2 is 827 amino acids long; isoform 2 is missing amino acids 240-318 from isoform 1. Isoform 1 is predicted to weigh 98 kDa and have an

isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). However, pI is also u ...

of 8.7, while isoform 2 is predicted to weigh 90 kDa and have an isoelectric point of 7.6. Other mammalian species also have multiple isoforms of SKIDA1, including

carnivorans Carnivora is a monophyletic order of placental mammals consisting of the most recent common ancestor of all cat-like and dog-like animals, and all descendants of that ancestor. Members of this group are formally referred to as carnivorans, ...

rodents Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are nat ...

, and

primates Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...

. The number of isoforms each species has varies: cheetahs have five recorded isoforms, chimpanzees have three recorded, and brown rats have two recorded. Skida1_3D_structure

Amino Acid Repeats

Human SKIDA1 contains two poly-alanine regions, one poly-histidine region, and one poly-glutamic acid region. It's unknown if they have any function. The poly-alanine and poly-histidine regions are not highly conserved among orthologs; for example, while they are found in the

house mouse The house mouse (''Mus musculus'') is a small mammal of the order Rodentia, characteristically having a pointed snout, large rounded ears, and a long and almost hairless tail. It is one of the most abundant species of the genus '' Mus''. Althoug ...

ortholog, they are not found in the

western lowland gorilla The western lowland gorilla (''Gorilla gorilla gorilla'') is one of two Critically Endangered subspecies of the western gorilla (''Gorilla gorilla'') that lives in Montane ecosystems#Montane forests, montane, Old-growth forest, primary and sec ...

ortholog. The poly-glutamic acid region shows more conservation, and is found abbreviated in species as distantly related from humans as the

tire track eel The zig-zag eel (''Mastacembelus armatus''), also known as the tire-track eel, tire-track spiny eel or marbled spiny eel, is a species of ray-finned, spiny eels belonging to the genus ''Mastacembelus'' (Scopoli, 1777) of the family Mastacembel ...

Domains

SKIDA1 contains two domains: Ski/Sno/Dac and DUF4854. The Ski/Sno/Dac domain is at the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

end of the protein. The Ski/Sno/Dac domain is also found in the proteins Ski, Ski-like protein, and dachshund. It is potentially a DNA-binding domain. The other domain, DUF4854, is also found in EPOP, near its

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

. However, the DUF4584 found in EPOP is roughly a fifth the size of that in SKIDA1. The C-termini of SKIDA1 (amino acids 844-908) and EPOP (amino acids 313-379) have 52% identity. The C-terminus of EPOP binds to the

SUZ12 Polycomb protein SUZ12 is a protein that in humans is encoded by the ''SUZ12'' gene. Function This zinc finger gene has been identified at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma. Recomb ...

subunit of

Polycomb Repressive Complex 2 Polycomb-group proteins (PcG proteins) are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes ...

(PRC2), suggesting that of SKIDA1 may as well.

Regulation

Promoter and Transcription Factors

In humans, there are five predicted potential promoters. Two align with the second half of the mRNA transcript, suggesting they are not used or only produce an incomplete polypeptide. The promoter that aligns best with the start of the mRNA transcript is potentially bound to by many transcription factors, including

Transcription factor II B Transcription factor II B (TFIIB) is a general transcription factor that is involved in the formation of the RNA polymerase II preinitiation complex (PIC) and aids in stimulating transcription initiation. TFIIB is localised to the nucleus and pro ...

, Nuclear factor Y, Early growth response 1, and Krueppel-like factor 6. It does not contain a TATA box.

Transcript Regulation

SKIDA1 is regulated by microRNAs. miR-93 binds to the SKIDA1

3'-UTR In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...

. Multiple microRNAs are predicted to bind to the SKIDA1 3'-UTR, including miR-130, miR-301, miR-454, and miR-494.

Polypeptide Modification

SKIDA1 is

SUMOylated In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (sometimes w ...

at five sites. Additional sites are predicted to be SUMOylated. SKIDA1 is also predicted to be phosphorylated and O-GlcNAcylated.

Expression

Subcellular Localization

SKIDA1 is predicted to be localized primarily in the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

and less so in the cytosol. SKIDA1_Purkinje

Tissue Expression

SKIDA1 is expressed at high levels in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

, and

testes A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoster ...

. It's expressed at medium to low levels in adipose tissue,

lymph nodes A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...

, and

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

. In mice, it's noted to have medium-to-high expression in the

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a grey matter, neural structure of the vertebrate forebrain involved in olfaction, the sense of odor, smell. It sends olfactory information to be further processed in the amygdala, the orbitof ...

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

, and salivary gland.

Developmental Expression

SKIDA1 expression changes during organism development. Expression is low in the

zygote A zygote (, ) is a eukaryotic cell formed by a fertilization event between two gametes. The zygote's genome is a combination of the DNA in each gamete, and contains all of the genetic information of a new individual organism. In multicellula ...

, peaks during

embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

, and is low post-birth. In the

, it's expressed most during organogenesis. In the fetus, its expression is low in the liver but not other organs. Expression in the adult liver is much higher. In contrast, SKIDA1 expression in the fetal brain is higher than in the adult brain. SKIDA1 in the African clawed frog is expressed faintly in the marginal zone of gastrulae. During

neurulation Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula. The process begins when the notochord induces the formati ...

, it's expressed in the brain and

cranial neural crest The cranial neural crest is one of the four regions of the neural crest. The cranial neural crest arises in the anterior and populates the face and the pharyngeal arches giving rise to bones, cartilage, nerves and connective tissue. The endocraniu ...

. During tailbud, SKIDA1 expression increases in sensory placodes. By the end of tailbud, neural expression has faded except in the olfactory organ.

Function

SKIDA1 is predicted to function primarily in the nucleus and also in the cytosol. SKIDA1 knockouts in mice have significant differences from wild-type mice in the skeletal, neurological, reproductive, and immune systems. Other significant differences include effected hearing, an enlarged thymus, and increased pre-weaning mortality. Some, but not all, of these effects were found in heterozygous knockouts.

Clinical significance

SKIDA1 expression is associated with multiple types of cancer. It is over-expressed in

epithelial ovarian cancer Surface epithelial-stromal tumors are a class of ovarian neoplasms that may be benign or malignant. Neoplasms in this group are thought to be derived from the ovarian surface epithelium (modified peritoneum) or from ectopic endometrial or Fallopi ...

cells. Its expression is altered by various cancer-treatment compounds: human alpha-lactalbumin made lethal to tumor cells; oleate salts; metformin; and

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

. In cell lines of cancerous cells, altered expression is associated with resistance to dasatinib and docetaxel, which are used to treat cancer. Altered methylation of SKIDA1 is associated with human

pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

, and lupus erythematosus. Additionally, SKIDA1 is expressed less in women with

Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...

compared to their identical twins without Down syndrome. Its expression is dramatically reduced in brains affected by untreated HIV1-associated neurocognitive disorders (HAND) in comparison to healthy brains and brains affected by HAND but treated with

antiretrovirals The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multipl ...

.{{cite journal , vauthors = Borjabad A, Morgello S, Chao W, Kim SY, Brooks AI, Murray J, Potash MJ, Volsky DJ , title = Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders , journal = PLOS Pathogens , volume = 7 , issue = 9 , pages = e1002213 , date = September 2011 , pmid = 21909266 , pmc = 3164642 , doi = 10.1371/journal.ppat.1002213 , editor-first = Ronald C. , editor-last = Desrosiers

References

Human proteins Human genes Genes on human chromosome 10 Proteins Genes Genes on human chromosome