Transposon hypothesis of carcinogenesis



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Abstract

The hypothesis is presented according to which the key drivers of carcinogenesis are transposons causing genomic instability, activation of oncogenes and inactivation of oncosuppressor genes. Expression of retroelements is under the negative regulatory control of proteins p53, RB1, VHL, BRCA1, ATM. It is assumed that most oncosuppressors have this property, since their genes are characterized by the presence in their composition of mobile elements (causing recombinations upon their activation) and hot spots of insertional mutagenesis. Accordingly, suppression of the expression of transposons as an adaptive process is necessary to ensure the stability of these genes. Therefore, the development of neoplasms in hereditary tumor syndromes may be due to pathological activation of transposons, which cause mutation of the second allele and other oncosuppressor genes due to congenital deficiency of oncosuppressor. Identical mechanisms are likely for sporadic carcinogenesis, when an activated transposon moves to new loci, causes complex genomic rearrangements specific to neoplasms, and inactivates oncosuppressors. Since the sequences of the transposable elements serve as alternative promoters for many genes, their activation causes enhanced expression of oncogenes in carcinogenesis. The transposons located in introns facilitate the transcription of chimeric molecules that have a pronounced oncogenic activity. In addition, mobile elements are sources of oncogenic microRNAs and long noncoding RNAs. The same microRNAs affect both neoplasms and aging, which confirms the hypothesis put forward, since dysregulation of mobile elements occurs with age, and aging is associated with an increased risk of cancer developing.

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R. N Mustafin

Bashkir State Medical University

Email: ruji79@mail.ru

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