CTDSPL (CTD (Carboxy-Terminal Domain, RNA Polymerase II, Polypeptide A) Small Phosphatase-Like)

2014-03-01 Shreya Sarkar , Guru Prasad Maiti , Chinmay Kumar Panda Affiliation

Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 S P Mukherjee Road, Kolkata - 700026, West Bengal, India

Identity

HGNC

CTDSPL

LOCATION

3p22.2

LOCUSID

10217

ALIAS

C3orf8,HYA22,PSR1,RBSP3,SCP3

FUSION GENES

Show Gene Fusions

DNA/RNA

Diagram shows the different transcripts of CTDSPL (Brown, Blue, Grey and Maroon boxes). Beginning of boxes represents transcription start sites. Filled areas represent translated regions. The larger form, CTDSPL B is shown as CTDSPL 001, whereas the smaller form, CTDSPL A is shown as CTDSPL 002. Image adapted from Ensembl.org.

Description

Located in the short (p) arm of chromosome 3, the length of the CTDSPL gene is about 122.5Kb, contains 8 exons and is arranged in a telomere to centromere orientation.

Transcription

The full length transcript of CTDSLP is 4459 bp (Ensembl,Transcript ID ENST00000443503). A total of 8 transcripts can be generated, out of which 5 are protein coding, 1 undergoes nonsense mediated decay, while the rest 2 do not code for a protein product. However, two splice variants of CTDSPL, the smaller CTDSPL A (lacking exon 3, therefore short of 33 bp, 11 amino acids) and the full length CTDSPL B were identified by Kashuba et al., 2004.
Interesting observation: The transcription start site for CTDSPL A and CTDSPL B are different (from ensemble.org). While the larger B form has a shorter 5UTR, the smaller A form has a larger 5UTR, although their translation start sites remain common. Difference in the size of the 5UTR may account for differential splicing between the isoforms.

Pseudogene

None reported.

Proteins

Schematic diagram of full length RBSP3 protein, showing different domains. Adapted from PDB O15194. Data origin/ Colour codes: Data in Green originates from UniProtKB; Data in Yellow originates from Pfam, by interacting with the HMMER3 website; Data in Grey has been calculated using BioJava. Protein disorder predictions are based on JRONN, a Java implementation of RONN. (a. Red- Potentially disordered region. b. Blue- Probably ordered region. Hydropathy has been calculated using a sliding window of 15 residues and summing up scored from standard hydrophobicity tables. a. Red- Hydrophobic. b. Blue- Hydrophilic); Data in blue originates from PDB. Secstruc- Secondary structure projected from representative PDB entries onto the UniProt sequence. (a. Red box - Helix. b. Yellow box - Sheet. c. Grey tube- Coil); Data in red indicates combined ranges of Homology Models from SBKB and the Protein Model Portal.

Description

The full length CTDSPL protein (CTDSPL B) is 276 amino acids in length, with a molecular weight of 31KD. The smaller protein, CTDSPL A is 265 amino acids in length (amino acids 79- 89 missing) and 29.9 KD in weight. Amino acids 102-260 contain the FCP1 homology domain, which contains an essential protein serine phosphatase that dephosphorylates the C-terminal domain (CTD) of RNA polymerase II.

CTDSPL Protein expression data from MOPED¹, PaxDb² and MAXQB³. 1. MOPED - Eugene Kolker, Bioinformatics & High-throughput Analysis Lab, Seattle Childrens Research Institute. 2. PaxDb - Christian von Mering, Bioinformatics Group, Institute of Molecular Life Sciences, University of Zurich. 3. MAXQB - Matthias Mann, Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Germany. The data was normalized as follows: 1. For each sample, ppm protein values were calculated, if not provided so by data sources. For each sample from MAXQB, iBAQ expression values were divided by sum of values of each sample, and multiplied by 1000000. For all samples, data was gene centrically aggregated by summing expression values of all isoforms for each gene. 2. For better visualization of graphs, expression values are drawn on a root scale, which is an intermediate between log and linear scales as used for our mRNA expression graphs (Safran et al., 2003).

Localisation

Both nuclear and cytoplasmic (Maiti et al., 2012; Sarkar et al., 2013).

Function

- CTDSPL is a serine phosphatase which regulates cell growth and differentiation. It dephosphorylates RB at serine 807/ 811 (hence called RB1 serine phosphatase from human chromosome 3), thereby increasing RB-E2F interaction and halting the cell cycle at G1/S boundary (Kashuba et al., 2004).
- It also inactivates RNA polymerase-II by preferential dephosphorylation of Ser-5 within the tandem 7 residues repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit, thus controlling the transcription machinery (hence called carboxy-terminal domain, RNA polymerase II, polypeptide A small phosphatase-like) (Yeo et al., 2003).
- Studies also suggest that CTDSPL/RBSP3 might function as a transcriptional co-repressor, inhibiting transcription of neuronal genes in non-neuronal cells (Yeo et al., 2005), and may also act as a phosphatase of Smad1, Smad2/Smad3 and Snail (Wu et al., 2009; Sapkota et al., 2006).

Homology

Chimpanzee, Rhesus monkey, dog, cow, mouse, chicken, zebrafish, S.cerevisiae, K.lactis, E.gossypii, S.pombe, M.oryzae, and N.crassa show conserved RBSP3 gene (Source NCBI homologene).
RBSP3 and miRNAs
1. miRNA 100
- RBSP3 is a bonafide target for miRNA 100.
- miRNA 100 binds to the 3`UTR of RBSP3 in regions conserved in humans, rats and mice.
- RBSP3 expression is inversely co-related with the expression of miRNA 100 in 76.5% AML cases.
2. miRNA 26a (has-miR-26a-1)
- miRNA 26a resides in the intron of RBSP3.
- It is concomitantly expressed with RBSP3 during the cell cycle.

Table : Different organisms showing homology in RBSP3 protein.

Figure: Interacting proteins of RBSP3, using String network.

Mutations

Mutations and copy number variations in different organs. Red bar: Loss. Grey bar: Gain. Adapted from COSMIC gene analysis.

Germinal

None reported.

Implicated in

Entity name

Cervical cancer

Note

- High deletion (48%, 45% cases) and methylation (26%, 25% cases) was seen in CIN and CACX respectively (Mitra et al., 2010).
- Reduced mRNA expression was seen in CACX (Mitra et al., 2010).
- Altogether, change in expression was in 79% of cases (Anedchenko et al., 2007). - In HPV infected cervical cancer, high deletion (42% cases) was observed, with significant variation (p

Prognosis

RBSP3 alterations (deletion, methylation) were significantly associated with poor patient outcome and posed 4.5-13 times risk of survival (Anedchenko et al., 2007).

Oncogenesis

Inactivation of RBSP3 was an early event in cervical carcinogenesis (Mitra et al., 2010).

Entity name

Breast cancer

Note

- Study population was divided into two groups, Group A (≤40 yrs, early onset) and Group B (>40 yrs, late onset) (Sinha et al., 2008).
- High deletion (30%, 24% cases) and methylation (38%, 32% cases) were observed in Groups A and B respectively (Sinha et al., 2008).
- 28.9 ± 39.1 fold reduction in expression of RBSP3 was observed in about 33 - 40% of the tumors (Sinha et al., 2008).
- Homozygous deletion (10-18%) was observed for RBSP3 (Senchenko et al., 2004).

Prognosis

Patients belonging lower to age of onset (≤40 yrs) with alterations of RBSP3 had poor disease outcome (Sinha et al., 2008).

Oncogenesis

Higher alterations of RBSP3 were observed in patients belonging to the lower age of onset (Group A) (Sinha et al., 2008).

Entity name

Acute lymphoid leukemia (ALL)

Note

Promoter methylation was seen in RBSP3 in 24% of ALL patients.

Entity name

Prostate cancer

Note

GWAS study using Affymetrix 100K SNP GeneChip with GEE model showed that the SNP, rs9311171 (G/ T), located within RBSP3, had a notable GEE p value (1.8x 10 ^-6).

Oncogenesis

GEE p value 1.8x 10 ^-6 indicates that this SNP within RBSP3 plays a role in tumor progression.

Entity name

Non - small cell lung cancer (NSCLC)

Note

- Reduction of expression of RBSP3 was obtained for both adenocarcinoma (AC) and squamous cell carcinoma (SCC) (Senchenko et al., 2008).
- Downregulation was both genetic and epigenetic (Senchenko et al., 2008).
- For ACs, decrease in level of expression was in 88% cases and 70% cases of metastatic and non-metastatic tumors respectively, whereas for SCCs, it was in 88% cases for both metastatic and non-metastatic tumors (Senchenko et al., 2008).
- Decrease in mRNA in ACs was due to deletion (25% cases) and promoter methylation (38% cases), whereas for SCCs, it was in 30% and 80% cases for deletion and methylation respectively (Senchenko et al., 2008).
- Fold decrease in expression of RBSP3 in AC and SCC was 78% and 88% respectively, with overall 85% decrease in expression of RBSP3 in NSCLC (Senchenko et al., 2010).

Oncogenesis

Deletion and methylation of promoter of RBSP3 are responsible for reduction in expression of the protein and play important roles in progression of NSCLC (Senchenko et al., 2008).
Reduction of expression of RBSP3 is required for development of lung adenocarcinomas (Senchenko et al., 2010).

Entity name

Ovarian cancer

Note

Deletion/Methylation of RBSP3 were observed in 33% cases.

Oncogenesis

RBSP3 deletion/methylation can be used as a biomarker for ovarian cancer in combination with other studied markers.

Entity name

Head and neck squamous cell carcinoma (HNSCC)

Note

- Deletion of RBSP3 in dysplasia and HNSCC was in 24% and 32% cases respectively (Ghosh et al., 2010).
- Promoter methylation was observed in 39% and 38% cases of dysplasia and HNSCC samples respectively (Ghosh et al., 2010).
- Fold reduction of mRNA in the tumors was 33.6 ± 9.4 (Ghosh et al., 2010).
- While normal tissues expressed the larger RBSP3 B form, tumors either showed no expression of RBSP3, or preferentially expressed the smaller, less active form, RBSP3 A (Ghosh et al., 2010).
Expression of RBSP3 decreases from pre-malignant to malignant lesions (Maiti et al., 2012).
Expression of RBSP3 was seen to be increased from pre-neoadjuvant chemotherapy tumors to post-therapy tumors (Sarkar et al., 2013).

Prognosis

Patients with RBSP3 alterations show poor survival (Ghosh et al., 2010).

Oncogenesis

Early alteration of RBSP3 takes place in head and neck cancers (Ghosh et al., 2010).
Loss of expression of RBSP3 was seen to be required for progression from malignant to invasive cancer (Maiti et al., 2012).
Regain of expression of RBSP3 in post-therapy tumors may be one of the reasons of shrinkage of tumors due to neoadjuvant chemotherapy (Sarkar et al., 2013).

Entity name

Lung, renal, breast, cervical and ovarian cancers

Note

High frequencies of somatic mutations in RBSP3 in different cancers suggesting it may underlay the mutator phenotype of cancer.

Entity name

Acute myeloid leukemia (AML)

Note

RBSP3 might have a crucial role in myeloid cell differentiation towards granulocyte/monocyte lineages through pRB-E2F pathway.

Entity name

Cell lines

Note

Leukemia cell lines RAJI, BJAB (B cell leukemia) and HL-60 (myeloid leukemia) showed hypermethylation of RBSP3 promoter.

Entity name

Hepatocellular carcinoma (HCC) in mouse model system

Note

RBSP3 shows increase in expression (RNA, protein) upon treatment with the chemopreventive agent Amarogentin.

Oncogenesis

Increase in expression of RBSP3 might play a role in chemoprevention upon treatment with amarogentin.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
19140316	2008	[Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer].	Anedchenko EA et al
20412120	2010	Frequent alterations of the candidate genes hMLH1, ITGA9 and RBSP3 in early dysplastic lesions of head and neck: clinical and prognostic significance.	Ghosh A et al
23202957	2012	NotI microarrays: novel epigenetic markers for early detection and prognosis of high grade serous ovarian cancer.	Kashuba V et al
19478941	2009	High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.	Kashuba VI et al
23167340	2012	Reduced expression of LIMD1 in ulcerative oral epithelium associated with tobacco and areca nut.	Maiti GP et al
19885927	2010	RBSP3 is frequently altered in premalignant cervical lesions: clinical and prognostic significance.	Mitra S et al
17903305	2007	A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study.	Murabito JM et al
22948180	2012	Prevention of liver carcinogenesis by amarogentin through modulation of G1/S cell cycle check point and induction of apoptosis.	Pal D et al
12543795	2003	An integrated physical and gene map of the 3.5-Mb chromosome 3p21.3 (AP20) region implicated in major human epithelial malignancies.	Protopopov A et al
12519968	2003	Human Gene-Centric Databases at the Weizmann Institute of Science: GeneCards, UDB, CroW 21 and HORDE.	Safran M et al
17085434	2006	Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways.	Sapkota G et al
24377544	2013	Reduction of proliferation and induction of apoptosis are associated with shrinkage of head and neck squamous cell carcinoma due to neoadjuvant chemotherapy.	Sarkar S et al
20193080	2010	Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer.	Senchenko VN et al
16707430	2006	Silencing of bidirectional promoters by DNA methylation in tumorigenesis.	Shu J et al
19016758	2008	Frequent alterations of hMLH1 and RBSP3/HYA22 at chromosomal 3p22.3 region in early and late-onset breast carcinoma: clinical and prognostic significance.	Sinha S et al
15681389	2005	Small CTD phosphatases function in silencing neuronal gene expression.	Yeo M et al
12721286	2003	A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5.	Yeo M et al
21643017	2012	MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.	Zheng YS et al
22210897	2012	MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein.	Zhu Y et al

Other Information

Locus ID:

NCBI: 10217
MIM: 608592
HGNC: 16890
Ensembl: ENSG00000144677

Variants:

dbSNP: 10217
ClinVar: 10217
TCGA: ENSG00000144677
COSMIC: CTDSPL

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000144677	ENST00000273179	O15194
ENSG00000144677	ENST00000416688	H7C2B9
ENSG00000144677	ENST00000435525	F8WED2
ENSG00000144677	ENST00000436654	H7C353
ENSG00000144677	ENST00000443503	O15194
ENSG00000144677	ENST00000447745	H7C2S4

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37341065	2023	Hsa-miR-503-5p regulates CTDSPL to accelerate cisplatin resistance and angiogenesis of lung adenocarcinoma cells.	0
37341065	2023	Hsa-miR-503-5p regulates CTDSPL to accelerate cisplatin resistance and angiogenesis of lung adenocarcinoma cells.	0
31774910	2019	Tumor suppressor properties of the small C-terminal domain phosphatases in non-small cell lung cancer.	8
31774910	2019	Tumor suppressor properties of the small C-terminal domain phosphatases in non-small cell lung cancer.	8
29382357	2018	The miR-181 family promotes cell cycle by targeting CTDSPL, a phosphatase-like tumor suppressor in uveal melanoma.	29
29672635	2018	Differential transmission of the molecular signature of RBSP3, LIMD1 and CDC25A in basal/ parabasal versus spinous of normal epithelium during head and neck tumorigenesis: A mechanistic study.	2
29382357	2018	The miR-181 family promotes cell cycle by targeting CTDSPL, a phosphatase-like tumor suppressor in uveal melanoma.	29
29672635	2018	Differential transmission of the molecular signature of RBSP3, LIMD1 and CDC25A in basal/ parabasal versus spinous of normal epithelium during head and neck tumorigenesis: A mechanistic study.	2
27414789	2016	[Interaction of two tumor suppressors: Phosphatase CTDSPL and Rb protein].	4
27458253	2016	Association of P16-RBSP3 inactivation with phosphorylated RB1 overexpression in basal-parabasal layers of normal cervix unchanged during CACX development.	1
27414789	2016	[Interaction of two tumor suppressors: Phosphatase CTDSPL and Rb protein].	4
27458253	2016	Association of P16-RBSP3 inactivation with phosphorylated RB1 overexpression in basal-parabasal layers of normal cervix unchanged during CACX development.	1
21643017	2012	MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.	56
21643017	2012	MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.	56
19885927	2010	RBSP3 is frequently altered in premalignant cervical lesions: clinical and prognostic significance.	13

Citation

Shreya Sarkar ; Guru Prasad Maiti ; Chinmay Kumar Panda

CTDSPL (CTD (Carboxy-Terminal Domain, RNA Polymerase II, Polypeptide A) Small Phosphatase-Like)

Atlas Genet Cytogenet Oncol Haematol. 2014-03-01

Online version: http://atlasgeneticsoncology.org/gene/40189/deep-insight-explorer/css/lib/hgnc