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

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

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

Identity

HGNC
LOCATION
3p22.2
LOCUSID
ALIAS
C3orf8,HYA22,PSR1,RBSP3,SCP3
FUSION GENES

DNA/RNA

Atlas Image
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

Atlas Image
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.
Atlas Image
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.
Atlas Image
Table : Different organisms showing homology in RBSP3 protein.
Figure: Interacting proteins of RBSP3, using String network.

Mutations

Atlas Image
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
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.

Bibliography

Pubmed IDLast YearTitleAuthors
191403162008[Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer].Anedchenko EA et al
204121202010Frequent 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
232029572012NotI microarrays: novel epigenetic markers for early detection and prognosis of high grade serous ovarian cancer.Kashuba V et al
194789412009High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.Kashuba VI et al
231673402012Reduced expression of LIMD1 in ulcerative oral epithelium associated with tobacco and areca nut.Maiti GP et al
198859272010RBSP3 is frequently altered in premalignant cervical lesions: clinical and prognostic significance.Mitra S et al
179033052007A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study.Murabito JM et al
229481802012Prevention of liver carcinogenesis by amarogentin through modulation of G1/S cell cycle check point and induction of apoptosis.Pal D et al
125437952003An 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
125199682003Human Gene-Centric Databases at the Weizmann Institute of Science: GeneCards, UDB, CroW 21 and HORDE.Safran M et al
170854342006Dephosphorylation 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
243775442013Reduction 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
201930802010Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer.Senchenko VN et al
167074302006Silencing of bidirectional promoters by DNA methylation in tumorigenesis.Shu J et al
190167582008Frequent 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
156813892005Small CTD phosphatases function in silencing neuronal gene expression.Yeo M et al
127212862003A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5.Yeo M et al
216430172012MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.Zheng YS et al
222108972012MicroRNA-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 IDTranscript IDUniprot
ENSG00000144677ENST00000273179O15194
ENSG00000144677ENST00000416688H7C2B9
ENSG00000144677ENST00000435525F8WED2
ENSG00000144677ENST00000436654H7C353
ENSG00000144677ENST00000443503O15194
ENSG00000144677ENST00000447745H7C2S4

Expression (GTEx)

0
10
20
30
40
50
60
70

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
190471282008Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma.99
170854342006Dephosphorylation 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.66
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
216430172012MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.49
150518892004RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies.29
201930802010Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer.23
204121202010Frequent alterations of the candidate genes hMLH1, ITGA9 and RBSP3 in early dysplastic lesions of head and neck: clinical and prognostic significance.19
194789412009High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.16
191403162008[Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer].15
198859272010RBSP3 is frequently altered in premalignant cervical lesions: clinical and prognostic significance.10

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/ctdspl