Транспозонная гипотеза канцерогенеза



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Аннотация

Представлена гипотеза, согласно которой ключевыми драйверами канцерогенеза являются транспозоны, вызывающие геномную нестабильность, экспрессию онкогенов и инактивацию онкосупрессорных генов. Экспрессия ретроэлементов находится под негативным регуляторным контролем белков р53, RB1, VHL, BRCA1, ATM. Предполагают, что большинство онкосупрессоров способны вызывать сайленсинг транспозонов, так как в их генах содержатся мобильные элементы, вызывающие рекомбинацию при их активации, и горячие точки инсерционного мутагенеза. Подавление экспрессии транспозонов онкосупрессорами в качестве адаптивного процесса к нормальному развитию организма, направленное на устранение возможности геномной нестабильности, необходимо для обеспечения стабильности этих генов. Причиной развития новообразований при наследственных опухолевых синдромах может стать обусловленная врожденным дефицитом онкосупрессора патологическая активация транспозонов, которые вызывают мутации второго аллеля и других онкосупрессорных генов. таким образом, при развитии опухолей формируется «порочный круг»: мобильные элементы инактивируют онкосупрессоры, необходимые для подавления экспрессии транспозонов, что вызывает активацию большего количества мобильных элементов и прогрессирующую геномную нестабильность, а вновь активированные транспозоны вызывают мутации в других онкосупрессорных генах. Идентичные механизмы вероятны для спорадического канцерогенеза: активированный под влиянием стрессовых факторов и соматических мутаций транспозон перемещается в новые локусы, вызывает характерные для неоплазм комплексные геномные перестройки, инактивирует онкосупрессоры, содержащие горячие точки инсерционного мутагенеза, и активирует онкогены, поскольку их регуляторные области и интроны содержат в своем составе транспозоны. расположенные в интронах транспозоны способствуют транскрипции химерных молекул, которые обладают выраженной онкогенной активностью. Кроме того, мобильные элементы являются источниками онкогенных микрорНК и длинных некодирующих рНК. одни и те же микрорНК влияют на развитие неоплазм и старение организма, что подтверждает гипотезу о роли транспозонов в канцерогенезе, так как с возрастом происходит активация транспозонов, а старение ассоциировано с высоким риском развития злокачественных опухолей.

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Р. Н Мустафин

Башкирский государственный медицинский университет

Email: ruji79@mail.ru

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