Paragenetic suppressors of suppressor genes - a new class of oncodeterminants

Impairment or loss of suppressor genes is a common event permitting the onc ogene/suppressor gene machinery to develop neoplasia. Following prenatal tr eatment with X-rays and UV-B, we detected a new class of oncodeterminants t hat could not be specified as genes. This points to paragenetic elements th at suppress suppressorgenes and thus provoke melanoma at earlier ages of on set as expected, with increased severity and increased number of incidences in successive generations, in the absence of further treatment. These elem ents were isolated from a xiphophorine DNA library by endogenously labeled long terminal repeats (LTR) of a xiphophorine retrovirus, and were characte rized as retrotransposons by Southern and Northern blotting and reverse tra nscription/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 fra mes (ORF) are flanked by LTR that contain genetically active regulatory ele ments, and are inducible by UV-B. ORF 3 shows nests of CG dinucleotides and CGG trinucleotides, which are reminiscent of CGG nests predisposing subjec ts to anticipation of certain human diseases involving tumor generation. Ge netic anticipation as defined by Nettleship (1909) or Warren (1996) includi ng an increase of neoplasia might represent an acquired genetic load in pre ceding generations, which might provide a lead to a molecular understanding of the worldwide increase of incidences of human tumor.