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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the SKIDA1

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

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

orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

vertebrates Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

. 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; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce 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 ...

, 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 ...

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

PRC2 PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1 ( Polycomb Repressive Complex 1). This complex has histone methyltransferase activity and ...

Homologs

Orthologs

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

lancelet The lancelets ( ), also known as amphioxi (: amphioxus ), consist of 32 described species of somewhat fish-like benthic filter feeding chordates in the subphylum Cephalochordata, class Leptocardii, and family Branchiostomatidae. Lancelets dive ...

''Branchiostoma belcheri''. The

clades In biology, a clade (), also known as a monophyletic group or natural group, is a group of organisms that is composed of a common ancestor and all of its descendants. Clades are the fundamental unit of cladistics, a modern approach to taxonomy ...

amphibia Amphibians are ectothermic, anamniotic, four-limbed vertebrate animals that constitute the class Amphibia. In its broadest sense, it is a paraphyletic group encompassing all tetrapods, but excluding the amniotes (tetrapods with an amniotic ...

and

chondrichthyes Chondrichthyes (; ) is a class of jawed fish that contains the cartilaginous fish or chondrichthyans, which all have skeletons primarily composed of cartilage. They can be contrasted with the Osteichthyes or ''bony fish'', which have skeleto ...

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 class Dipnoi. Lungfish are best known for retaining ancestral characteristics within the Osteichthyes, including the ability to breathe air, and ancestral structures within Sarcopterygii, inc ...

invertebrate Invertebrates are animals that neither develop nor retain a vertebral column (commonly known as a ''spine'' or ''backbone''), which evolved from the notochord. It is a paraphyletic grouping including all animals excluding the chordata, chordate s ...

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 or sausage dog, badger dog, doxen and doxie, is a short-legged, long-bodied, hound-type dog breed. The dog may be smooth-haired, wire-haired, or long-haired, with varie ...

(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 Chromosome 10 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 10 spans about 134 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...

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 i ...

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 and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

. 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 electric charge, electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). Howe ...

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 an Order (biology), order of Placentalia, placental mammals specialized primarily in eating flesh, whose members are formally referred to as carnivorans. The order Carnivora is the sixth largest order of mammals, comprising at ...

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 n ...

, and

primates Primates is an order of mammals, which is further divided into the strepsirrhines, which include lemurs, galagos, and lorisids; and the haplorhines, which include tarsiers and simians ( monkeys and apes). Primates arose 74–63 ...

. The number of isoforms each species has varies:

cheetahs The cheetah (''Acinonyx jubatus'') is a large cat and the fastest land animal. It has a tawny to creamy white or pale buff fur that is marked with evenly spaced, solid black spots. The head is small and rounded, with a short snout and blac ...

have five recorded isoforms,

chimpanzees The chimpanzee (; ''Pan troglodytes''), also simply known as the chimp, is a species of great ape native to the forests and savannahs of tropical Africa. It has four confirmed subspecies and a fifth proposed one. When its close relative the ...

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

; for example, while they are found in the

house mouse The house mouse (''Mus musculus'') is a small mammal of the rodent family Muridae, 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''. A ...

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'' Scopoli, 1777'), also known as the Baim, tire-track, tire-track spiny-eel, freshwater spiny eel, or marbled spiny eel, is a species of freshwater ray-finned fish in the family Mastacembelidae. It is nat ...

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 amin ...

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, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

. 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. Recom ...

subunit of

Polycomb Repressive Complex 2 PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1 (Polycomb Repressive Complex 1). This complex has histone methyltransferase activity and pr ...

(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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...

, 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 p ...

, Nuclear factor Y,

Early growth response 1 EGR-1 (Early growth response protein 1) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene. EGR-1 is a mammalian transcription factor. It was also named Krox-24, TIS8, and ZENK. It was or ...

, and Krueppel-like factor 6. It does not contain a

TATA box In molecular biology, the TATA box (also called the Goldberg–Hogness box) is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has a ...

Transcript Regulation

SKIDA1 is regulated by

microRNAs Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcri ...

. miR-93 binds to the SKIDA1 3'-UTR. 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 at five sites. Additional sites are predicted to be SUMOylated. SKIDA1 is also predicted to be

phosphorylated In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

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 Nucleu ...

and less so in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

Tissue Expression

SKIDA1 is expressed at high levels in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...

, and

testes A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...

. It's expressed at medium to low levels in

adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

lymph nodes A lymph node, or lymph gland, is a kidney-shaped Organ (anatomy), 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 lymphoc ...

, and

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

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

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

retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...

, and

salivary gland The salivary glands in many vertebrates including mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands ( parotid, submandibular, and sublingual), as well as hundreds of min ...

Developmental Expression

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

zygote A zygote (; , ) is a eukaryote, eukaryotic cell (biology), 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 individ ...

, peaks during

embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...

, and is low post-birth. In the

, it's expressed most during

organogenesis Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal org ...

. 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 The African clawed frog (''Xenopus laevis''), also known as simply xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African Aquatic animal, aquatic frog of the family Pipidae. Its name is derived from the ...

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 :wikt:ectopic, ectopic endometri ...

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

metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, ...

; and

aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

. In cell lines of cancerous cells, altered expression is associated with resistance to

dasatinib Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that a ...

and

docetaxel Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cel ...

, 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 ...

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

, and

lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, ...

. Additionally, SKIDA1 is expressed less in women with Down syndrome 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 mul ...

.{{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 , doi-access = free

References

Human proteins Genes on human chromosome 10 Proteins Genes Human genes