Ген дигидрофолатредуктазы человека имеет два промотора и необычный принцип регуляции. Основной промотор, отвечающий за синтез 99% мРНК DHFR, работает при активном росте клеток. Если рост клеток замедляется, то включается второй промотор, расположенный непосредственно перед основным промотором. Продукт экспрессии минорного промотора DHFR - некодирующая РНК. Эта РНК ингибирует активность основного промотора, однако, каким образом это ей удается - оставалось загадкой.

Механизм своеобразной "войны промоторов" раскрыли в группе Александра Акуличева в Оксфорде. Оказывается, некодирующая РНК препятствует сборке преинициаторного комплекса РНК-полимеразы II, взаимодействуя с одним из его компонентов - TFIIB. Более того, некодирующая РНК способна напрямую связываться с промоторной областью гена DHFR. Группе Акуличева удалось показать специфическое взаимодействие некодирующей РНК с TFIIB in vitro с помощью гель-шифтов и in vivo при помощи РНК-ChIP.

Механизм ингибирования основного промотора DHFR напоминает феномен эпигенетической регуляции промоторов с помощью малых РНК, искусственно введенных в клетку. По ряду причин многие из статей, посвященные описанию этого феномена, были отозваны. Остается надеяться, что работа группы Акуличева не последует их печальному примеру.

Ссылки по теме:

• Статья Martianov I. et al., Nature. (2007); 445:666-70
• Александр Акуличев.

На рис. - минорный промотор гена DHFR подавляет активность мажорного промотора. Этот эффект можно наблюдать in trans. Все дело в некодирующей РНК. Рис из статьи. Martianov I et al., Nature. (2007); 445:666-70

Интересно, какое строение у этого "верхнего" промотора? Эта некодирующая РНК не может синтезироваться РНК-полимеразой III, как B2-РНК, которая тоже ингибирует РНК-полимеразу II?

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