Paragenetic suppressors of suppressor genes - a new class of oncodeterminants

Abstract

Impairment or loss of suppressor genes is a common event permitting the oncogene/suppressor gene machinery to develop neoplasia. Following prenatal treatment with X-rays and UV-B, we detected a new class of oncodeterminants that could not be specified as genes. This points to paragenetic elements that suppress suppressorgenes and thus provoke melanoma at earlier ages of onset as expected, with increased severity and increased number of incidences in successive generations, in the absence of further treatment. These elements were isolated from a xiphophorine DNA library by endogenously labeled long terminal repeats (LTR) of a xiphophorine retrovirus, and were characterized as retrotransposons by Southern and Northern blotting and reverse transcription/polymerase chain reaction and transient transfection studies, in situ hybridization, and sequencing. They appear in multiple copies in the telomeric chromosome regions, where they can extend. Three open reading frames (ORF) are flanked by LTR that contain genetically active regulatory elements, and are inducible by UV-B. ORF 3 shows nests of CG dinucleotides and CGG trinucleotides, which are reminiscent of CGG nests predisposing subjects to anticipation of certain human diseases involving tumor generation. Genetic anticipation as defined by Nettleship (1909) or Warren (1996) including an increase of neoplasia might represent an acquired genetic load in preceding generations, which might provide a lead to a molecular understanding of the worldwide increase of incidences of human tumor.

Amplification of a long terminal repeat-like element on the Y chromosome of the platyfish, Xiphophorus maculatus

“…1) from the ONCXmrk locus on the Y chromosome were isolated and cosmid D18 097 was partially sequenced. A sequence presenting 88% nucleotide identity with the 5′ long-terminal-repeat (LTR) of the Xiphophorus XIR retrotransposon (GenBank accession number S77502, Anders et al 1994;Roushdy et al 1999) was identified about 45 kb upstream from ONC-Xmrk. Other than this no associated sequence was found with significant similarities to typical retroelement genes such as reverse transcriptase.…”