Distinct organization of the candidate tumor suppressor gene RFP2 in human and mouse: multiple mRNA isoforms in both species- and human-specific antisense transcript RFP2OS

Baranova, Ancha; Hammarsund, Marianne; Ivanov, Dmitry; Skoblov, Mikhail; Sangfelt, Olle; Corcoran, Martin; Borodina, Tatiana; Makeeva, Natalia; Pestova, Anna; Tyazhelova, T. V.; Nazarenko, Svetlana; Gorreta, Francesco; Alsheddi, Tariq; Schlauch, Karen; Никитин, Е. А.; Kapanadze, Bagrat; Shagin, Dmitry A.; Полтараус, А. Б.; Vorobiev, Andrey Ivanovich; Zabarovsky, Eugene R.; Luk'ianov, S A; Chandhoke, Vikas; Ibbotson, Rachel; Oscier, David; Einhorn, Stefan; Grandér, Dan; Yankovsky, N. K.

doi:10.1016/j.gene.2003.08.007

Cited by 34 publications

(39 citation statements)

References 25 publications

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“…In allelic exclusion, one allele is silenced to ensure that the complex process of Ig gene recombination takes place only once. In 13q14.3, others and we observed excessive splicing of all large ncRNA genes (3,10,11). Because only genes from one of the chromosomes are expressed in 13q14.3, it is tempting to speculate that transcriptional and posttranscriptional complexity of the critical region requires silencing of the second chromosome similar to the Ig locus.…”

Section: Discussionmentioning

confidence: 77%

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

Mertens¹,

Wolf²,

Tschuch³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Genomic material from chromosome band 13q14.3 distal to the retinoblastoma locus is recurrently lost in a variety of human neoplasms, indicating an as-yet-unidentified tumor-suppressor mechanism. No pathogenic mutations have been found in the minimally deleted region until now. However, in B cell chronic lymphocytic leukemia tumors with loss of one copy of the critical region, respective candidate tumor-suppressor genes are downregulated by a factor >2, which would be expected by a normal gene-dosage effect. This finding points to an epigenetic pathomechanism. We find that the two copies of the critical region replicate asynchronously, suggesting differential chromatin packaging of the two copies of 13q14.3. Although we also detect monoallelic silencing of genes localized in the critical region, monoallelic expression originates from either the maternal or paternal copy, excluding an imprinting mechanism. DNA methylation analyses revealed one CpG island of the region to be methylated. DNA demethylation of this CpG island and global histone hyperacetylation induced biallelic expression, whereas replication timing was not affected. We propose that differential replication timing represents an early epigenetic mark that distinguishes the two copies of 13q14.3, resulting in differential chromatin packaging and monoallelic expression. Accordingly, deletion of the single active copy of 13q14.3 results in significant downregulation of the candidate genes and loss of function, providing a model for the interaction of genetic lesions and epigenetic silencing at 13q14.3 in B cell chronic lymphocytic leukemia.DNA methylation ͉ monoallelic expression ͉ replication timing

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Section: Discussionmentioning

confidence: 77%

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

Mertens¹,

Wolf²,

Tschuch³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Cloning and sequence analysis of the 5′-genomic region of the RFP2 gene Human cosmid clone LANL116c1 was identified previously by Southern hybridization as one that contains RFP2 [1]. Clone LANL116c1 was digested by HindIII, EcoRI, and BamHI digestion enzymes separately and in combinations.…”

Section: Methodsmentioning

confidence: 99%

“…Human RFP2 consists of three exons, with exon 1 included in mRNA as longer or shorter variant (exon 1a and exon 1b) [1]. Complete open-reading frame of RFP2 (407 aa) is located inside exon 3 the only coding exon.…”

mentioning

confidence: 99%

“…1). First, 5′-untranslated exons of RFP2 overlap with the untranslated opposite strand transcript RFP2OS [1]. Second, the 3′-untranslated part of RFP2 exon 3 overlaps with the promoter area and exon 1 of another gene, KCNRG, encoding a protein with high homology to tetramerization domain of voltage-gated K+ channels that suppresses K+ channel activity [6].…”

mentioning

confidence: 99%

“…As these genes are encoded by the same DNA strand, it is possible that expression of RFP2 interferes with the initiation of KCNRG transcription. Third, comparative studies of the promoter area and the 5′-untranslated area of RFP2 in rodents revealed DNA rearrangements that lead to an absence of any sequence homology to human RFP2 in the non-coding parts of mouse and rat orthologues [1].…”

mentioning

confidence: 99%

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Human RFP2 gene promoter: Unique structure and unusual strength

Skoblov

Shakhbazov

Oshchepkov

et al. 2006

Biochemical and Biophysical Research Communications

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Human gene RFP2 is a candidate tumor suppressor located at 13q14.3 and deleted in multiple tumor types. To explore regulation of RFP2, we determined structure of the 5′-untranslated region of RFP2 gene and its promoter. RFP2 promoter area is TATA-less, highly enriched in G and C nucleotides, and contains multiple quadruplex forming GGGGA-repeats. Deletion analysis of 5′-flanking sequences demonstrated that repeat containing fragment possesses activity seven times exceeding that of the combined SV40 promoter/enhancer. Other unusual features of the RFP2 promoter include anomalously high electrostatic fields induced by sequence-dependent dipoles and very low nucleosome forming potential. A "minimized" version of the RFP2 promoter could be used for overexpression of the various transgenes in the mammalian cells.

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DLEU2 encodes an antisense RNA for the putative bicistronic RFP2/LEU5 gene in humans and mouse

Corcoran

Hammarsund²,

Zhu³

et al. 2004

Genes Chromosomes & Cancer

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Our group previously identified two novel genes, RFP2/LEU5 and DLEU2, within a 13q14.3 genomic region of loss seen in various malignancies. However, no specific inactivating mutations were found in these or other genes in the vicinity of the deletion, suggesting that a nonclassical tumor-suppressor mechanism may be involved. Here, we present data showing that the DLEU2 gene encodes a putative noncoding antisense RNA, with one exon directly overlapping the first exon of the RFP2/LEU5 gene in the opposite orientation. In addition, the RFP2/LEU5 transcript can be alternatively spliced to produce either several monocistronic transcripts or a putative bicistronic transcript encoding two separate open-reading frames, adding to the complexity of the locus. The finding that these gene structures are conserved in the mouse, including the putative bicistronic RFP2/LEU5 transcript as well as the antisense relationship with DLEU2, further underlines the significance of this unusual organization and suggests a biological function for DLEU2 in the regulation of RFP2/LEU5.

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Distinct organization of the candidate tumor suppressor gene RFP2 in human and mouse: multiple mRNA isoforms in both species- and human-specific antisense transcript RFP2OS

Cited by 34 publications

References 25 publications

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism

Human RFP2 gene promoter: Unique structure and unusual strength

DLEU2 encodes an antisense RNA for the putative bicistronic RFP2/LEU5 gene in humans and mouse

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