|Written||2014-07||Ping Chen, Qi Chen|
|Department of genetics, Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China (PC); Department of Pharmacology, Toxicology,, Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA (QC)|
(Note : for Links provided by Atlas : click)
|chromosome 6 open reading frame 210|
|Location||6q21 [Link to chromosome band 6q21]|
|Location_base_pair||Starts at 107152557 and ends at 107459575 bp from pter ( according to hg19-Feb_2009) [Mapping PDSS2.png]|
|Local_order||According to NCBI Map Viewer, several genes flank PDSS2 in the order from centromere to telomere direction on chromosome: 6; NC_000006.11:
- C6orf203, chromosome 6 open reading frame 203, location: 6q21;
- BEND3, BEN domain containing 3, location: 6q21;
- RPS24P12, ribosomal protein S24 pseudogene 12, location: 6q21;
- PDSS2, 6q21;
- SOBP, sineoculis binding protein homolog (Drosophila), location: 6q21.
|Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)|
|AP1S3 (2q36.1) / PDSS2 (6q21)||ATG5 (6q21) / PDSS2 (6q21)||MAN1A1 (6q22.31) / PDSS2 (6q21)|
|PDSS2 (6q21) / PDSS2 (6q21)||PDSS2 (6q21) / SMARCA4 (19p13.2)|
|Diagram of the PDSS2 gene (isoform1/Dlp1). Exons are represented by open boxes (in yellow). Exons 1 to 8 are from the 5' to 3' direction.|
|Description||PDSS2 gene has 307.02 kb of genomic DNA on the reverse strand, containing 8 exons.|
|Transcription||The full transcript is a 3568 bp mRNA with 1200 bp open reading frame. This gene has 4 transcripts (splice variants, PDSS2-001 to 004). All transcripts are protein coding. The length of the 4 splice variants are 3540 bp (399 aa), 1338 bp (297 aa), 1236 bp (240 aa) and 241 bp (80 aa) respectively.|
|Note|| Human decaprenyl diphosphate synthase is a hetero-tetramer composed of DPS1 (PDSS1; NM_014317) and DLP1 (PDSS2) subunits that produces the ubiquinone coenzyme Q10. |
The isoprenoid chain of ubiquinone (coenzyme Q) varies in length between species and is determined by trans-polyprenyl diphosphate synthase.
Other names: decaprenyl pyrophosphate synthetase subunit 2; prenyl diphosphate synthase, subunit 2; subunit 2 of decaprenyl diphosphate synthase.
|Diagram of 2 isoforms of PDSS2 protein (DLP1and DLP2).|
|Description|| The complete translation product is a 44 kDa protein containing 399 amino acids. It is the non-catalyzing subunit of prenyl diphosphate synthase, the first enzyme in CoQ10 biosynthesis. However it is essential for the activity of the enzyme. Its mutations could cause CoQ10 deficiency and contributes to nephritic and metabolic diseases and neuromuscular defects.|
It is also a candidate tumor suppressor protein, and was found down-regulated in melanoma, gastric cancer and non-small-cell lung cancers.
A mutated protein was identified by Saiki et al. (2005) that contains the 7 conserved domains typically found in all trans-prenyl diphosphate synthases, but it lacks DDxxD motifs which could be involved in the catalytic mechanism and/or the binding of the substrates.
|Expression|| According to AceView, this gene is expressed at high level, 2.1 times the average genes, observed from 226 cDNA clones.|
Northern blot analysis shows PDSS2 expresses two transcripts: 3.5 and 1.2 kb. The 3.5-kb transcript was expressed strongly in heart, prostate, and testis; moderately in brain, kidney, liver, lung, spleen, duodenum, esophagus, pancreas, thymus, and thyroid; and weakly in colon, muscle, small intestine, salivary gland, and uterus, and was absent in stomach, peripheral blood lymphocyte, and urinary bladder. Expression of the 1.2-kb transcript was detected in heart, kidney, liver, pancreas, prostate, testis, thymus, and thyroid.
|Localisation||Cytoplasm, organelle, mitochondria.|
|Function|| It is the 2nd subunit of decaprenyl diphosphate synthase, which catalyzes the first and critical step in coenzyme Q biosynthesis: the formation of all trans-polyprenyl pyrophosphates from isopentyl diphosphate in the assembly of polyisoprenoid side chains. The step is critical in coenzyme Q biosynthesis. It is not the catalytic subunit but is essential for the catalytic activity. |
Related super-pathways: Metabolic pathways, apoptosis, geranyldiphosphate biosynthesis, trans-octaprenyl transferase activity and protein heterodimerization activity.
Protein interaction: PDSS2 protein can interact with apoptotic protease-activating factor 1 (APAF1, DIP27624N), which mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the ATP required activation of caspase-3 and apoptosis. Result from in silicon pathway analysis showed that PDSS2 protein could interact with hepatocyte nuclear factor 4 alpha (HNF4a), a nuclear transcription factor which regulates the expression of many genes involved in cell growth and proliferation.
|Homology||PDSS2 gene is conserved in human, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and mosquito.|
|Note|| PDSS2, GLN322TER [dbSNP:rs118203955] |
PDSS2, SER382LEU [dbSNP:rs118203956]
Disease: Primary coenzyme Q10 deficiency-3 (COQ10D3; OMIM614652).
Two compound heterozygous mutations in the PDSS2 gene were identified by López et al. (2006) in an infant with fatal encephalomyopathy and nephrotic syndrome due to coenzyme Q10 deficiency-3 (COQ10D3; 614652): 2 mutations in the PDSS2 gene: a 964C-T transition resulting in a gln322-to-ter (Q322X,610564.0001) substitution inherited from the unaffected father; and a 1145C-T transition resulting in a ser382-to-leu (S382L; 610564.0002) substitution in the seventh conserved domain inherited from the unaffected mother (López et al., 2006).
In fibroblasts derived from the patient reported by López et al. (2006). CoQ10 levels were decreased to 22.4% of normal, and the cells showed reduced ATP levels (50% of controls), but no increase in reactive oxygen species, signs of oxidative stress, increased antioxidant defense markers,or oxidative stress-induced cell death (Quinzii et al., 2008; Quinzii et al., 2010). This suggested that the pathology caused by these PDSS2 mutations was related to the marked bioenergetic defect, but not to oxidative stress. The very low mitochondrial respiratory activity may even confer some resistance to stress-induced apoptosis.
5. Implicated in
|Note|| PDSS2 may be a potent gastric cancer growth suppressor in vitro acting through apoptosis pathways. By transfecting PDSS2 to gastric cancer cell line SGC7901, Chen et al. found that expression of PDSS2 can induce apoptosis in human gastric cancer SGC7901 cells, block cell at G0/G1 stage, and inhibit cell proliferation. |
Expression of PDSS2 is downregulated in human gastric cancer (84.6%, 33/39), and the degree of expression degraded with the increase of malignant degree of tumor. In poorly differentiated gastric cancer, the negative or low expression of PDSS2 was 35% (7/20) or 55% (11/20) and in moderately differentiated gastric cancer, it was 10.5% (2/19) or 68.4% (13/19), respectively (Chen et al., 2009).
|Note|| Down-regulation of PDSS2 was observed in 59 of 87 (67.8%) primary melanomas, which was significantly higher than that in benign nevi (7 of 66, 10.6%). An overexpression of the PDSS2 in UACC-903 cells could inhibit tumor cell growth, decrease the colony-forming ability in soft agar, and totally abrogate the tumorigenicity of UACC-903 in nude mice. Fung et al. proposed that PDSS2 is a novel tumor suppressor gene that plays an important role in the development of malignant melanoma (Fung et al., 2009). |
The sequence of PDSS2 (AF254956) was firstly submitted to National Cancer for Biotechnology Information by the authors in 2000 and was then named as C6orf210 by Human Genome Organization. Then C6orf210 was found to be important in determining the length of the side chain of ubiquinone in mammals and was named as PDSS2 (Saiki et al., 2005).
|Entity||Non-small cell lung cancer|
|Note|| Non-small cell carcinomas (NSCLC) are divided into non-small cell lung cancer accounts for approximately 85% of all lung cancers. It is divided further into three main categories: adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma histologies. 6q16.3-21 LOH has been found in 78% of SCLCs. PDSS2 gene is located in the frequent LOH region of 6q16.3-21, implying for its potential role as tumor suppressor. Loss of PDSS2 expression is associated with non-small cell lung cancer. Decrease in PDSS2 expression was more severe in poorly and poor-to-moderately differentiated lung cancers, more in higher pathological stage and in patients with lymph node metastasis. The decrease in PDSS2 expression in tumor tissues was not related to sex or histological type of NSCLC, but was related to smoking history (Chen et al., 2013). |
The PDSS2 gene has low expression levels in human lung cancer cell lines. The forced PDSS2 overexpression caused massive cell death through apoptotic pathways and significantly inhibited colony formation in the NCI-H1299 lung cancer cell line. At the same time, repression of PDSS2 expression by siRNA enhanced the growth of a noncancerous lung epithelial cell line MRC-5. There was an inverse correlation between PDSS2 expression and gelsolin expression, which is known to inhibit apoptosis and enhance cell invasion and metastasis. The ability of PDSS2 to repress gelsolin might contribute to its tumor-suppressing activity. However, PDSS2 did not influence the sensitivity of the lung cancer cells to chemotherapeutic drugs. Taken together, PDSS2 has tumor-suppressing activity in human lung cancer cells by enhancing apoptosis and inhibiting tumorigenic capacity (Chen et al., 2014).
|Diagram of PDSS2 possible pathway involved in produce lung cancer cells death through apoptosis.|
|Note|| Studies have reported the potential of the PDSS2 gene as a tumor suppressor in gastric cancer, lung cancer, and melanoma. First, the PDSS2 gene is located in the chromosome region of 6q16.3-21, where frequent LOH occurs in lung cancers, implying the loss of PDSS2 expression and function in lung cancers. Second, PDSS2 protein is essential for the enzyme activity of prenyl diphosphate synthase, which is a critical enzyme in CoQ10 biosynthesis. Decreased PDSS2 level can lead to CoQ10 deficiency. CoQ10 is the predominant human form of endogenous ubiquinone, and plays a vital role in the mitochondrial respiratory chain as the carrier of electrons from complexes I and II to complex III. Its reduced form is one of the most potent lipophilic antioxidants in all cell membranes. CoQ10 also participates in pyrimidine nucleoside biosynthesis and may modulate apoptosis and the mitochondrial uncoupling protein. By depletion of CoQ10, decrease in PDSS2 may contribute toward the initiation and progression of tumor through deregulated mitochondria function and increased intracellular oxidative stress. |
Overexpression of PDSS2 induced apoptosis in cancer cells. The mechanism is not clear. A possible mechanism could be that CoQs including CoQ10 can selectively inhibit DNA topoisomerase II (topo-II) activity and eukaryotic DNA polymerase-γ, which is a mitochondrial DNA polymerase, and thus inhibit DNA synthesis and mitochondrial proliferation and consequently induce cancer cell death.
An inverse correlation of PDSS2 expression and gelsolin expression was reported. Gelsolin has been shown to inhibit apoptosis by blocking mitochondrial membrane potential loss and cytochrome c release, thus stabilizing mitochondria. Repression of gelsolin by PDSS2 may counteract the mitochondrial stabilization, and thus induce apoptosis in cancer cells.
PDSS2 does not influence the chemosensitivity of lung cancer cells.
|Decrease of PDSS2 expression, a novel tumor suppressor, in non-small cell lung cancer.|
|Chen P, Yu J, Knecht J, Chen Q.|
|Cancer Epidemiol. 2013 Apr;37(2):166-71. doi: 10.1016/j.canep.2012.12.004. Epub 2013 Jan 10.|
|The tumor-suppressing activity of the prenyl diphosphate synthase subunit 2 gene in lung cancer cells.|
|Chen P, Zhang Y, Polireddy K, Chen Q.|
|Anticancer Drugs. 2014 Aug;25(7):790-8. doi: 10.1097/CAD.0000000000000105.|
|Anticancer activity of PDSS2, prenyl diphosphate synthase, subunit 2, in gastric cancer tissue and the SGC7901 cell line.|
|Chen P, Zhao SH, Chu YL, Xu K, Zhu L, Wu Y, Song J, Cao CX, Xue X, Niu YY.|
|Anticancer Drugs. 2009 Feb;20(2):141-8. doi: 10.1097/CAD.0b013e32832016a9.|
|COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement.|
|Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi G, Piemonte F, Montini G, Ghiggeri GM, Murer L, Barisoni L, Pastore A, Muda AO, Valente ML, Bertini E, Emma F.|
|J Am Soc Nephrol. 2007 Oct;18(10):2773-80. Epub 2007 Sep 12.|
|Identification and characterization of a novel melanoma tumor suppressor gene on human chromosome 6q21.|
|Fung JM, Smith R, Brown MA, Lau SH, Xie D, Lau GK, Guan XY.|
|Clin Cancer Res. 2009 Feb 1;15(3):797-803. doi: 10.1158/1078-0432.CCR-08-1472.|
|Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10.|
|Gasser DL, Winkler CA, Peng M, An P, McKenzie LM, Kirk GD, Shi Y, Xie LX, Marbois BN, Clarke CF, Kopp JB.|
|Am J Physiol Renal Physiol. 2013 Oct 15;305(8):F1228-38. doi: 10.1152/ajprenal.00143.2013. Epub 2013 Aug 7.|
|Characterization of a complex chromosome rearrangement involving 6q in a melanoma cell line by chromosome microdissection.|
|Guan XY, Zhang HE, Zhou H, Sham JS, Fung JM, Trent JM.|
|Cancer Genet Cytogenet. 2002 Apr 1;134(1):65-70.|
|Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers.|
|Lauc G, Huffman JE, Pucic M, Zgaga L, Adamczyk B, Muzinic A, Novokmet M, Polasek O, Gornik O, Kristic J, Keser T, Vitart V, Scheijen B, Uh HW, Molokhia M, Patrick AL, McKeigue P, Kolcic I, Lukic IK, Swann O, van Leeuwen FN, Ruhaak LR, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, de Craen AJ, Deelder AM, Zeng Q, Wang W, Hastie ND, Gyllensten U, Wilson JF, Wuhrer M, Wright AF, Rudd PM, Hayward C, Aulchenko Y, Campbell H, Rudan I.|
|PLoS Genet. 2013;9(1):e1003225. doi: 10.1371/journal.pgen.1003225. Epub 2013 Jan 31.|
|Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations.|
|Lopez LC, Schuelke M, Quinzii CM, Kanki T, Rodenburg RJ, Naini A, Dimauro S, Hirano M.|
|Am J Hum Genet. 2006 Dec;79(6):1125-9. Epub 2006 Oct 27.|
|Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood.|
|Lu S, Lu LY, Liu MF, Yuan QJ, Sham MH, Guan XY, Huang JD.|
|Neurobiol Dis. 2012 Jan;45(1):219-33. doi: 10.1016/j.nbd.2011.08.006. Epub 2011 Aug 10.|
|Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome.|
|Machuca E, Benoit G, Nevo F, Tete MJ, Gribouval O, Pawtowski A, Brandstrom P, Loirat C, Niaudet P, Gubler MC, Antignac C.|
|J Am Soc Nephrol. 2010 Jul;21(7):1209-17. doi: 10.1681/ASN.2009121309. Epub 2010 May 27.|
|Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease.|
|Peng M, Falk MJ, Haase VH, King R, Polyak E, Selak M, Yudkoff M, Hancock WW, Meade R, Saiki R, Lunceford AL, Clarke CF, Gasser DL.|
|PLoS Genet. 2008 Apr 25;4(4):e1000061. doi: 10.1371/journal.pgen.1000061.|
|Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency.|
|Quinzii CM, Lopez LC, Gilkerson RW, Dorado B, Coku J, Naini AB, Lagier-Tourenne C, Schuelke M, Salviati L, Carrozzo R, Santorelli F, Rahman S, Tazir M, Koenig M, DiMauro S, Hirano M.|
|FASEB J. 2010 Oct;24(10):3733-43. doi: 10.1096/fj.09-152728. Epub 2010 May 21.|
|Characterization of solanesyl and decaprenyl diphosphate synthases in mice and humans.|
|Saiki R, Nagata A, Kainou T, Matsuda H, Kawamukai M.|
|FEBS J. 2005 Nov;272(21):5606-22.|
|This paper should be referenced as such :|
|P Chen, Q Chen|
|PDSS2 (prenyl (decaprenyl) diphosphate synthase, subunit 2)|
|Atlas Genet Cytogenet Oncol Haematol. 2015;19(4):286-290.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/PDSS2ID890ch6q21.html|
|Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]|
9. External links
|REVIEW articles||automatic search in PubMed|
|Last year publications||automatic search in PubMed|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Thu Jan 17 19:04:11 CET 2019|
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