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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review RNASET2 (ribonuclease T2) Francesco Acquati, Paola Campomenosi Dipartimento di Biotecnologie e Scienze Molecolari, Universita degli Studi dell'Insubria, I-21100 Varese, Italy Published in Atlas Database: February 2007 Online updated version: http://AtlasGeneticsOncology.org/Genes/RNASET2ID518ch6q27.html DOI: 10.4267/2042/38446 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology kb of genomic DNA. The translation initiation codon is located to exon 1 and the stop codon to exon 9. Exons III and VI encode the two CAS motifs (Catalytic Active Sites) responsible for the ribonuclease activity of the RNASET2 protein. Identity Hugo: RNASET2 Other names: RNASE6PL; RP11-514O12.3; bA514O12.3 Location: 6q27 Local order: Telomeric to RPS6KA2, centromeric to FGFR1OP. Note: This gene is the first human member of the Rh/T2/S-glycoprotein family of extracellular ribonucleases. It is a putative class II tumor suppressor gene potentially involved in the pathogenesis of several solid and haematologic human neoplasias such as ovarian cancer, melanoma and non-Hodgkin lymphoma. Transcription The RNASET2 gene is transcribed in the telomere-tocentromere orientation to produce an ubiquitously expressed mRNA approximately 1,4 kb in length. EST clones representing splice variants of the same gene have been described. Pseudogene A processed pseudogene showing 85% identity with RNASET2 mRNA maps to chromosome 7p11.2. The expression pattern of this pseudogene is not known. DNA/RNA Description This gene is split in 9 exons spanning approximatly 27 I-IX: RNASET2 exons. Atlas Genet Cytogenet Oncol Haematol. 2007;11(3) 219 RNASET2 (ribonuclease T2) Acquati F, Campomenosi P tumorigenicity and metastasis when overexpressed in the same ovarian cancer cell lines. Such results have been recently confirmed in a human melanoma cell line. Protein Description The full-length RNASET2 protein contains 256 aminoacids and displays an apparent MW of 36 kDa in its secreted form. Two 31 and 27 kDa C-terminal proteolytic products have also been observed intracellularly in several human cancer cell lines and localize to the lysosome. Homology The primary sequenze of RNASET2 shows strong homology to the Rh/T2/S family of secreted ribonucleases. Mutations Expression Expression of the RNASET2 protein has been detected in several human ovarian cancer cell lines and in some melanoma, prostate, pancreatic and breast carcinoma cell lines. Germinal A common exon-9 missense C708T germline mutation has been described but no evidence for an association of this allele with human cancer was found. Localisation Somatic The RNASET2 protein can be detected either intracellularly within lysosomes and secretory pathway, or extracellularly in a secreted form (in cell culture supernatants). A few common polymorphisms in exons 1, 8 and 9 have been described. Implicated in Function Human ovarian carcinoma Biochemical function: RNASET2 is an acid ribonuclease with optimal activity at pH 5 and preferential cleavage of poly-A and poly-U homopolyribonucleotides. Biological function: RNASET2 behaves as a class II tumor suppressor gene for ovarian cancer, since experimental overexpression of this gene in human ovarian cancer cell lines is associated with a significant decrease of their tumorigenic and metastasizing potential in vivo. Strikingly, the ribonuclease catalytic activity is apparently dispensable for RNASET2 to play such antioncogenic role. Indeed, a double CAS mutant cDNA construct encoding an almost inactive RNASET2 protein is still able to suppress Atlas Genet Cytogenet Oncol Haematol. 2007;11(3) Disease Loss of expression of RNASET2 occurs in a significant fraction of human ovarian cancer cell lines and primary ovarian tumours. When overexpressed by gene transfer experiments in human ovarian cancer cell lines displaying a low level of endogenous mRNA, RNASET2 strongly suppresses the tumorigenic and metastatic potential of these cell lines in vivo. Cytogenetics The RNASET2 genes maps in a genomic region (6q27) which is frequently deleted or otherwise rearranged in a wide range of human neoplasias, including ovarian cancer. 220 RNASET2 (ribonuclease T2) Acquati F, Campomenosi P References localization of the human homolog of the R2/Th/Stylar ribonuclease gene family. Methods Mol Biol 2001;160:87-101. Trubia M, Sessa L, Taramelli R. Mammalian Rh/T2/Sglycoprotein ribonuclease family genes: cloning of a human member located in a region of chromosome 6 (6q27) frequently deleted in human malignancies. Genomics 1997;42:342-344. Acquati F, Possati L, Ferrante L, Campomenosi P, Talevi S, Bardelli S, Margiotta C, Russo A, Bortoletto E, Rocchetti R, Calza R, Cinquetti R, Monti L, Salis S, Barbanti-Brodano G, Taramelli R. Tumor and metastasis suppression by the human RNASET2 gene. Int J Oncol 2005;26:1159-1168. Acquati F, Morelli C, Cinquetti R, Bianchi MG, Porrini D, Varesco L, Gismondi V, Rocchetti R, Talevi S, Possati L, Magnanini C, Tibiletti MG, Bernasconi B, Daidone MG, Shridhar V, Smith DI, Negrini M, Barbanti-Brodano G, Taramelli R. Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27. Oncogene 2001;20:980-988. Campomenosi P, Salis S, Lindqvist C, Mariani D, Nordström T, Acquati F, Taramelli R. Characterization of RNASET2, the first human member of the Rh/T2/S family of glycoproteins. Arch Biochem Biophys 2006;449:17-26. This article should be referenced as such: Acquati F, Campomenosi P. RNASET2 (ribonuclease T2). Atlas Genet Cytogenet Oncol Haematol.2007;11(3):219-221. Acquati F, Nucci C, Bianchi MG, Gorletta T, Taramelli R. Molecular cloning, tissue distribution, and chromosomal Atlas Genet Cytogenet Oncol Haematol. 2007;11(3) 221