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SCAF1 (SR-related CTD-associated factor 1)

Written2020-04Katerina Katsaraki, Andreas Scorilas, Christos K. Kontos
Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Faculty of Biology, Athens, Greece / chkontos@biol.uoa.gr
This article is an update of :
2010-03Christos Kontos, Andreas Scorilas
Department of Biochemistry, Molecular Biology, Faculty of Biology, University of Athens, 157 01, Panepistimiopolis, Athens, Greece

Abstract Review on SCAF1, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords SCAF1; RNA splicing; Breast cancer; Ovarian cancer; Colon cancer; Acute promyelocytic leukemia; glomerulosclerosis

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Identity

Alias (NCBI)SR-A1
HGNC (Hugo) SCAF1
HGNC Alias symbSR-A1
FLJ00034
LocusID (NCBI) 9169
Atlas_Id 46074
Location 19q13.33  [Link to chromosome band 19q13]
Location_base_pair Starts at 49642209 and ends at 49658642 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping SCAF1.png]
Local_order Telomere to centromere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note The first name of this gene, discovered and cloned by Scorilas et al. was SR-A1. After the establishment of the name "SRA1" for steroid receptor RNA activator 1, the official name of SR-A1 gene has changed into SCAF1, to avoid confusion.

DNA/RNA

 
  Figure 1. Schematic representation of the SCAF1 transcripts. Exons are shown as boxes and introns as connecting lines. Protein coding exons are shown as red boxes. Arrows show the positions of the start codon and asterisks show the positions of the stop codon. Numbers in parentheses indicate lengths of protein isoforms. Question marks (?) indicate that the 5' end of the sequence was not determined. The numbers inside boxes indicate exon lengths and the numbers over the horizontal lines show the intron lengths (in bp). The two slash lines (//) indicate regions not drawn to scale.
Description Spanning 18.2 kb of genomic DNA, the SCAF1 gene consists of 13 exons and 12 intervening introns.
Transcription Twenty-three transcripts of the SCAF1 gene have been annotated. The primary transcript (SCAF1 v.1; GenBank accession number: NM_021228.3) has a length of 4222 bp and an open reading frame (ORF) (Scorilas et al., 2001). This transcript is widely present in many normal tissues, with its levels varying importantly. The highest levels of SCAF1 v.1 were detected in fetal brain and fetal liver and the lowest in salivary gland, skin, heart, uterus, and ovary. In the mammary and prostate gland, SCAF1 v.1 is constitutively present at relatively high levels. Additionally, SCAF1 v.1 levels are increased in cancer cell lines treated with various steroid hormones, including estrogens, androgens and glucocorticoids, and to a lesser extent with progestins (Scorilas et al., 2001).
Recently, members of our research group discovered fifteen new SCAF1 transcripts (SCAF1 v.2 - v.16; GenBank accession numbers: KY849380.1 - KY849394.1), resulting from alternative splicing of the SCAF1 pre-mRNAs (Adamopoulos et al., 2018). These splice variants are much shorter compared to main transcript, as all of them lack exon 9. They show a wide expression profile in several cancerous and normal cells. Seven out of these fifteen SCAF1 splice variants seem to have an ORF, whereas the remaining eight novel transcripts contain a premature termination codon and thus represent non-sense-mediated mRNA decay (NMD) candidates.
Bioinformatic analysis of expressed sequence tags (ETSs) revealed three additional splice variants (v.X1, X2, and X3), all of which are predicted to be protein-coding. These transcripts have different 5' untranslated regions (5' UTRs), compared to aforementioned transcripts. Moreover, four partial sequences have been deposited in the Ensembl (accession numbers: ENST00000601038.5 and ENST00000595242.3) or GenBank databases (accession numbers: BC011662.2 and BQ896877.1).
Pseudogene Not identified so far.

Protein

Description The full-length SCAF1 protein is composed of 1312 amino acid residues, with a calculated molecular mass of 139.3 kDa and a theoretical isoelectric point of 9.31 (Scorilas et al., 2001). It contains an Arg/Ser-rich domain as well as a CTD-binding domain, which is present only in a subset of Arg/Ser-rich splicing factors. Through interactions with the pre-mRNA and the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), Arg/Ser-rich proteins have been shown to regulate alternative splicing (Scorilas et al., 2001; Katsarou et al., 2005). Moreover, it has been observed that Arg/Ser-rich proteins may participate in tumorigenesis by regulating alternative splicing of several mRNAs. In addition, two areas with negatively charged polyglutamic acid (E) stretches and an Arg/Asp-rich motif are present in the full-length protein sequence. This motif is also present in a number of other RNA-binding proteins such as the small nuclear ribonucleoprotein U1 subunit 70 (SNRNP70), the negative elongation factor complex member E (NELFE), and the 68 kDa human pre-mRNA cleavage factor Im (CPSF6).
Examination of the hydrophobicity profile of the primary SCAF1 protein did not reveal regions with long stretches of hydrophobic residues (Scorilas et al., 2001). Various putative post-translational modification sites have been identified, including numerous potential sites for either O- or N-glycosylation, N-myristoylation, as well as phosphorylation by protein kinase A (PKA), protein kinase C (PKC), and casein kinase 2 (CSNK2).
Seven SCAF1 protein isoforms are likely to be encoded by splice variants of this gene. These protein isoforms are expected to have completely different secondary structures. Interestingly, they lack the Arg/Ser-rich domain and are hence unlikely to be involved in the regulation of alternative splicing (Adamopoulos et al., 2018).
 
  Figure 2. Schematic representation of the amino acid sequence of the full-length SCAF1 protein. Regions being reach in particular amino-acid residues, motifs, and domains are shown with colored boxes. Specific binding sites and putative post-translational modification sites are shown in bold, with different colors.
Expression Currently, there are no data concerning the in vivo expression of the human SCAF1 protein.
 
  Figure 3. Predicted model of the SCAF1 protein, using the I-TASSER server (Yang and Zhang, 2015). Only the 3D structure with the highest confidence score is presented. The RasMol 'Group' color scheme color codes residues by their position in a macromolecular chain. The protein is drawn as a smooth spectrum from blue through green, yellow and orange to red. Thus, the N-terminus is colored blue and the C-terminus is drawn in red.
Localisation The SCAF1 protein is predicted to be localized to the nucleus (Scorilas et al., 2001).
Function SCAF1 interacts with the CTD domain of the RNA polymerase II polypeptide A (POLR2A) and is involved in pre-mRNA splicing (Katsarou et al., 2005).
Homology Human SCAF1 shares 85% amino acid identity and 91% similarity with the mouse and rat Scaf1 protein. Moreover, it shows 25% identity and 48% similarity with the human PHD and ring finger domains 1 protein (PHRF1), and to a lesser extent with other Arg/Ser-rich splicing factors (Scorilas et al., 2001).

Mutations

Germinal SCAF1 was mutated in some cases of patients with familial focal and segmental glomerulosclerosis, a histologically defined pattern of kidney injury (Wang et al., 2019).
Somatic A single nucleotide polymorphism (SNP), rs12104272, located within the first intron of the SCAF1 gene, is be associated with liver cirrhosis in patients with hepatitis C virus. Specifically, the majority of patients with hepatitis C that were carriers of this dominant allele, did not exhibit liver cirrhosis (Real et al., 2014). SCAF1 was also mutated in some cases of patients with pulmonary sarcomatoid carcinoma. Specifically, alterations either without predicted effect or with deleterious effect were observed (Liu et al., 2016). Moreover, SCAF1 was mutated in some cases of patients with sporadic focal and segmental glomerulosclerosis, a histologically defined pattern of kidney injury (Wang et al., 2019).

Implicated in

Note
  
Entity Ovarian cancer
Prognosis Expression analysis of the SCAF1 gene has showed that SCAF1 mRNA expression may be considered as a new prognostic marker for ovarian cancer. Regarding SCAF1 gene expression in ovarian cancer, it is positively related to the histological grade and stage of the disease, the size of the tumor, and the debulking success. Additionally, high SCAF1 expression is a significant independent unfavorable prognostic marker of overall survival (OS), as low mRNA expression of the gene is related to longer disease-free survival (DFS) and OS. Moreover, SCAF1 overexpression is associated with clinically more aggressive ovarian cancer. The differential expression of SCAF1 in ovarian tumors suggests its involvement in the ovarian tumor progression (Scorilas et al., 2001; Leoutsakou et al., 2006a).
  
  
Entity Breast cancer
Prognosis Expression analysis of the SCAF1 gene showed that SCAF1 mRNA expression may be considered as a new unfavorable prognostic marker for breast cancer as low SCAF1 mRNA expression is associated with longer DFS and OS. Furthermore, the expression of the SCAF1 gene in breast cancer tissues is influenced by the tumor size and lymph node metastasis (Leoutsakou et al., 2006b).
  
  
Entity Colon cancer
Note The SCAF1 gene has been found overexpressed in colon cancer tissues compared to normal mucosa.
Prognosis SCAF1 mRNA expression seems to be associated with colon cancer progression, since its expression is higher at the initial stages of tumorigenesis and decreases along with cancer progression (advanced tumor grade, increased tumor size, cancer cell metastasis). Additionally, high SCAF1 mRNA expression may constitute a favorable prognosticator for the disease, as it is associated with longer DFS (Mathioudaki et al., 2004).
  
  
Entity Acute promyelocytic leukemia
Note Alterations of the SCAF1 mRNA expression have been observed in the human acute promyelocytic leukemia cell line HL-60, after treatment with cisplatin and bleomycin. mRNA levels of SCAF1 are modulated in both cases as a response to apoptosis induction by each drug (Katsarou et al., 2007). This differential response of SCAF1 mRNA levels to apoptosis induced by each drug may be due to distinct apoptotic pathways and, thus, to distinct cellular needs for the splice variants of specific genes.
Cytogenetics No cytogenetic abnormalities have been identified so far.
Hybrid/Mutated Gene Not identified so far.
  

Bibliography

Discovery and expression analysis of novel transcripts of the human SR-related CTD-associated factor 1 (SCAF1) gene in human cancer cells using Next-Generation Sequencing
Adamopoulos PG, Raptis GD, Kontos CK, Scorilas A
Gene 2018 Sep 5;670:155-165
PMID 29787824
 
Effect of bleomycin and cisplatin on the expression profile of SRA1, a novel member of pre-mRNA splicing factors, in HL-60 human promyelocytic leukemia cells
Katsarou ME, Thomadaki H, Katsaros N, Scorilas A
Biol Chem 2007 Aug;388(8):773-8
PMID 17655495
 
Prognostic significance of the expression of SR-A1, encoding a novel SR-related CTD-associated factor, in breast cancer
Leoutsakou T, Talieri M, Scorilas A
Biol Chem 2006 Dec;387(12):1613-8
PMID 17132108
 
Next-Generation Sequencing of Pulmonary Sarcomatoid Carcinoma Reveals High Frequency of Actionable MET Gene Mutations
Liu X, Jia Y, Stoopler MB, Shen Y, Cheng H, Chen J, Mansukhani M, Koul S, Halmos B, Borczuk AC
J Clin Oncol 2016 Mar 10;34(8):794-802
PMID 26215952
 
SR-A1, a member of the human pre-mRNA splicing factor family, and its expression in colon cancer progression
Mathioudaki K, Leotsakou T, Papadokostopoulou A, Paraskevas E, Ardavanis A, Talieri M, Scorilas A
Biol Chem 2004 Sep;385(9):785-90
PMID 15493872
 
A polymorphism linked to RRAS, SCAF1, IRF3 and BCL2L12 genes is associated with cirrhosis in hepatitis C virus carriers
Real LM, Caruz A, Rivero-Juarez A, Soriano V, Neukam K, Rivero A, Cifuentes C, Mira JA, Macías J, Pineda JA
Liver Int 2014 Apr;34(4):558-66
PMID 24131527
 
Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer
Scorilas A, Kyriakopoulou L, Katsaros D, Diamandis EP
Br J Cancer 2001 Jul 20;85(2):190-8
PMID 11461075
 
Contributions of Rare Gene Variants to Familial and Sporadic FSGS
Wang M, Chun J, Genovese G, Knob AU, Benjamin A, Wilkins MS, Friedman DJ, Appel GB, Lifton RP, Mane S, Pollak MR
J Am Soc Nephrol 2019 Sep;30(9):1625-1640
PMID 31308072
 
I-TASSER server: new development for protein structure and function predictions
Yang J, Zhang Y
Nucleic Acids Res 2015 Jul 1;43(W1):W174-81
PMID 25883148
 

Citation

This paper should be referenced as such :
Katsaraki K, Scorilas A, Kontos CK
SCAF1 (SR-related CTD-associated factor 1)
Atlas Genet Cytogenet Oncol Haematol. 2021;25(1):52-56.
Free journal version : [ pdf ]   [ DOI ]
History of this paper:
Kontos, C ; Scorilas, A. SCAF1 (SR-related CTD-associated factor 1). Atlas Genet Cytogenet Oncol Haematol. 2010;14(12):1149-1151.
http://documents.irevues.inist.fr/bitstream/handle/2042/44918/03-2010-SCAF1ID46074ch19q13.pdf


External links

 

Nomenclature
HGNC (Hugo)SCAF1   30403
Cards
AtlasSCAF1ID46074ch19q13
Entrez_Gene (NCBI)SCAF1    SR-related CTD associated factor 1
AliasesSRA1
GeneCards (Weizmann)SCAF1
Ensembl hg19 (Hinxton)ENSG00000126461 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000126461 [Gene_View]  ENSG00000126461 [Sequence]  chr19:49642209-49658642 [Contig_View]  SCAF1 [Vega]
ICGC DataPortalENSG00000126461
TCGA cBioPortalSCAF1
AceView (NCBI)SCAF1
Genatlas (Paris)SCAF1
SOURCE (Princeton)SCAF1
Genetics Home Reference (NIH)SCAF1
Genomic and cartography
GoldenPath hg38 (UCSC)SCAF1  -     chr19:49642209-49658642 +  19q13.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SCAF1  -     19q13.33   [Description]    (hg19-Feb_2009)
GoldenPathSCAF1 - 19q13.33 [CytoView hg19]  SCAF1 - 19q13.33 [CytoView hg38]
ImmunoBaseENSG00000126461
Genome Data Viewer NCBISCAF1 [Mapview hg19]  
OMIM617264   
Gene and transcription
Genbank (Entrez)AK024444 BC011662 BC018398 BC023628 BC053992
RefSeq transcript (Entrez)NM_021228
Consensus coding sequences : CCDS (NCBI)SCAF1
Gene ExpressionSCAF1 [ NCBI-GEO ]   SCAF1 [ EBI - ARRAY_EXPRESS ]   SCAF1 [ SEEK ]   SCAF1 [ MEM ]
Gene Expression Viewer (FireBrowse)SCAF1 [ Firebrowse - Broad ]
GenevisibleExpression of SCAF1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9169
GTEX Portal (Tissue expression)SCAF1
Human Protein AtlasENSG00000126461-SCAF1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9H7N4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9H7N4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9H7N4
PhosPhoSitePlusQ9H7N4
Domains : Interpro (EBI)SCAF1   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)SCAF1
SuperfamilyQ9H7N4
AlphaFold pdb e-kbQ9H7N4   
Human Protein Atlas [tissue]ENSG00000126461-SCAF1 [tissue]
HPRD11604
Protein Interaction databases
DIP (DOE-UCLA)Q9H7N4
IntAct (EBI)Q9H7N4
BioGRIDSCAF1
STRING (EMBL)SCAF1
ZODIACSCAF1
Ontologies - Pathways
QuickGOQ9H7N4
Ontology : AmiGORNA binding  protein binding  nucleus  transcription by RNA polymerase II  mRNA processing  RNA splicing  protein domain specific binding  RNA polymerase II C-terminal domain binding  RNA polymerase II C-terminal domain binding  
Ontology : EGO-EBIRNA binding  protein binding  nucleus  transcription by RNA polymerase II  mRNA processing  RNA splicing  protein domain specific binding  RNA polymerase II C-terminal domain binding  RNA polymerase II C-terminal domain binding  
NDEx NetworkSCAF1
Atlas of Cancer Signalling NetworkSCAF1
Wikipedia pathwaysSCAF1
Orthology - Evolution
OrthoDB9169
GeneTree (enSembl)ENSG00000126461
Phylogenetic Trees/Animal Genes : TreeFamSCAF1
Homologs : HomoloGeneSCAF1
Homology/Alignments : Family Browser (UCSC)SCAF1
Gene fusions - Rearrangements
Fusion : MitelmanSCAF1::FLT3LG [19q13.33/19q13.33]  
Fusion : MitelmanSCAF1::MAP4K1 [19q13.33/19q13.2]  
Fusion : MitelmanSCAF1::TRAPPC6A [19q13.33/19q13.32]  
Fusion : MitelmanVAMP8::SCAF1 [2p11.2/19q13.33]  
Fusion : QuiverSCAF1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSCAF1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SCAF1
dbVarSCAF1
ClinVarSCAF1
MonarchSCAF1
1000_GenomesSCAF1 
Exome Variant ServerSCAF1
GNOMAD BrowserENSG00000126461
Varsome BrowserSCAF1
ACMGSCAF1 variants
VarityQ9H7N4
Genomic Variants (DGV)SCAF1 [DGVbeta]
DECIPHERSCAF1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSCAF1 
Mutations
ICGC Data PortalSCAF1 
TCGA Data PortalSCAF1 
Broad Tumor PortalSCAF1
OASIS PortalSCAF1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSCAF1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DSCAF1
Mutations and Diseases : HGMDSCAF1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaSCAF1
DgiDB (Drug Gene Interaction Database)SCAF1
DoCM (Curated mutations)SCAF1
CIViC (Clinical Interpretations of Variants in Cancer)SCAF1
NCG (London)SCAF1
Cancer3DSCAF1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM617264   
Orphanet
DisGeNETSCAF1
MedgenSCAF1
Genetic Testing Registry SCAF1
NextProtQ9H7N4 [Medical]
GENETestsSCAF1
Target ValidationSCAF1
Huge Navigator SCAF1 [HugePedia]
ClinGenSCAF1
Clinical trials, drugs, therapy
MyCancerGenomeSCAF1
Protein Interactions : CTDSCAF1
Pharm GKB GenePA162402459
PharosQ9H7N4
Clinical trialSCAF1
Miscellaneous
canSAR (ICR)SCAF1
HarmonizomeSCAF1
DataMed IndexSCAF1
Probes
Litterature
PubMed42 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXSCAF1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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