Identifizierung und Charakterisierung von Retrosequenzen der tumorrelevanten HMGA Gene im menschlichen Genom
Blank, Cornelia
Universität Bremen: Biologie/Chemie
Retropseudogene, Retrogene, Retrotransposition, Integration, High Mobility Group Proteine, Genfamilie, Tumorgenese
Retrosequences of protein-coding genes are generated by retrotransposition, i.e. reverse transcription of the genes´ mRNAs followed by integration into the genome. More than 8.000 genomic cDNA copies from an estimated total of 20.000 have been identified so far in human. Their biological relevance depends on the function of their respective (retrotranscribed) gene, on their own transcriptional status (active: retrogene / inactive: retropseudogene), but also on their integration site. The high mobility group protein (HMG) gene family is regarded as one of the largest retrosequence families in human. This thesis represents the first detailed study of retrosequences of a complete HMG group, i.e. HMGA. HMGA proteins play an important role in cell differentiation and tumorigenesis making possible active retrosequences of their genes interesting subjects. During the study 7 retrosequences of HMGA1 located on different chromosomes could be identified and characterised in detail concerning their formation, integration, transcriptional status and their possible role in tumorigenesis. They were derived from 5 different mRNA splice variants from which 2 have not been cloned yet. Their retrotransposition appeared to have been catalysed by the L1 endonuclease/reverse transcriptase ("target primed reverse transcription"). In silico analyses revealed 3 transcriptionally active retrosequences in normal and pathogenic tissues. At least one of them represents a new exon of an unknown gene. Concerning a possile relevance of the retrosequences for tumor initiation and / or progression 2 hypotheses were tested by analyzing chromosomal aberrations in cases of several solid benign tumor entities. The first hypothesis implied an own tumor-inducing potential of the retrosequences as proto-oncogenes. Whereas the second one suggested a mutational influence on the tumor-related HMGA genes by homologous recombination as aberration partners. Statistical analyses supported both hypotheses.
hbi 820
Identifizierung und Charakterisierung von Retrosequenzen der tumorrelevanten HMGA Gene im menschlichen Genom
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