Роль ВТВ-содержащих белков Mod(mdg4) и GAF в функционировании инсулятора Su(Hw) у Drosophila melanogaster тема диссертации и автореферата по ВАК РФ 03.00.02, кандидат физико-математических наук Мазур, Александр Михайлович

• Мазур, Александр Михайлович
• кандидат физико-математических наук
• 2004

Оглавление диссертации кандидат физико-математических наук Мазур, Александр Михайлович

1. ВВЕДЕНИЕ.

2. ОБЗОР ЛИТЕРАТУРЫ.

2.1. Модели экспрессии генов.

2.2. Структура и функции инсуляторов.

2.3. Модели действия инсуляторов.

2.4. Белки с ВТВ доменами.

2.5. Структура и свойства белков 5и(Н\у) инсулятора.

3. МАТЕРИАЛЫ И МЕТОДЫ.

3.1. Реактивы.

3.2. Ферменты.

3.3. Праймеры.

3.4. Бактериальные и дрожжевые штаммы и плазмидные ДНК.

3.5. Культивирование бактерий и дрожжей.

3.6. Получение компетентных клеток для трансформации плазмидной ДНК методом электропорации.

3.7. Трансформация компетентных клеток плазмидной ДНК (электропорация).

3.8. Выделение плазмидной ДНК.

3.9. Электрофорез ДНК в агарозном геле.

3.10. Расщепление ДНК эндонуклеазами рестрикции.

3.11. Лигирование ДНК.

3.12. Тупление выступающих концов ДНК.

3.13. Получение мутаций в гене mod(mdg4).

3.14. Получение делеции в гене mod(mdg4).

3.15. Получение векторов для двугибридной системы.

3.16. Трансформация дрожжевых клеток.

3.17. Анализ взаимодействий в двугибридной системе.

3.18. Синтез и выделение белков.

3.19. Электрофорез белков в денатурирующем 8% ПААГ.

3.20. Электрофорез белков в нативном 7% ПААГ.

3.21. Перенос и детекция белков на мембране.

3.22. Генетические скрещивания.

3.23. Детекция белков на политенных хромосомах дрозофилы.

3.24. Детекция белков в клетках имагинальных дисков дрозофилы.

4. РЕЗУЛЬТАТЫ.

4.1. Наличие точечных замен в "заряженном кармане" не влияет на способность белка взаимодействовать с 8и(Н\у) и димеризоваться.

4.2. Белок Мо<3(тс^4) содержит второй домен, отвечающий за димеризацию.

4.3. Функциональная активность мутантных форм белка в работе инсулятора Би(Нш).

4.4. Локализация белков на политенных хромосомах и в ядерных тельцах диплоидных клеток.

5. ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ.

6. ВЫВОДЫ.

Введение диссертации (часть автореферата) на тему «Роль ВТВ-содержащих белков Mod(mdg4) и GAF в функционировании инсулятора Su(Hw) у Drosophila melanogaster»

Геном высших эукариот содержит огромное количество генов и их регуляторных элементов, таких как энхансеры, сайленсеры и инсуляторы. Энхансеры могут активировать транскрипцию гена независимо от ориентации, находясь при этом от промотора на расстоянии, которое может достигать нескольких сотен тысяч пар нуклеотидов. Многие энхансеры не имеют специфичности к определенному промотору и способны активировать транскрипцию с целого ряда генов. Так как в геноме гены располагаются часто достаточно близко друг к другу, то должны существовать механизмы, обеспечивающие взаимодействие энхансера с промотором своего гена и предотвращающие активацию чужих промоторов. В определении взаимодействий между энхансерами и промоторами важную роль играют инсуляторы и сайленсеры. Инсуляторы блокируют взаимодействие между энхансером и промотором, находясь между ними. При этом они не влияют на активность самих энхансеров и промоторов, т.е. промотор может быть активирован любым неизолированным энхансером, а энхансер может активировать любой другой неизолированный промотор. В то же время, репрессирующее действие сайленсеров не зависит от пространственного расположения по отношению к энхансеру или промотору.

В выяснении механизма действия инсуляторов большую роль сыграло определение белков, ответственных за функцию инсуляторов. Впервые белки, блокирующие взаимодействие между энхансером и промотором, были охарактеризованы для инсулятора su(Hw), который находится в составе мобильного элемента МДГ4 {gypsy). Этот инсулятор содержит 12 сайтов связывания для одного белка, кодируемого геном su(Hw).

Инактивация данного гена приводит к потере инсуляции. Сила инсулятора напрямую зависит от количества сайтов связывания белка Su(Hw). Делеция даже нескольких сайтов связывания резко снижает эффективность действия инсулятора. Белок Su(Hw) имеет на концах домены, обогащенные кислыми аминокислотными остатками и ДНК-связывающий домен, состоящий из 12 цинковых пальцев. Ранее были получены мутации в регуляторном гене mod(mdg4). Один из белков, Мос1(т(1§4)-67.2, который кодируется геном mod(mdg4), взаимодействует с доменом белка 8и(Н\у), отвечающем за инсуляцию. На Г^-конце белка Мос1(тс^4)-67.2 находится ВТВ/РОг домен, который может мультимеризоваться и взаимодействовать с другими белковыми комплексами. На С-конце белка Мос1(тс1£4)-67.2 находится кислый домен, который взаимодействует с доменом белка 8и(Н\у), являющийся критичным для инсуляции. Мутация mod(mdg4)ul, приводящая к инактивации взаимодействия белков Мос1(т(%4)и1 и 8и(Н\у), в одних случаях снижает активность 8и(Н\у) инсулятора, а в других - превращает 8и(Н\у) инсулятор в репрессор транскрипции. Существующая модель работы инсулятора предполагает, что оба белка необходимы для работы инсулятора. Считается, что в результате взаимодействия между ВТВ доменами белков Мос1(тс^4)-67.2, связанных с разными 8и(Н\у) инсуляторами, происходит формирование инсуляторных комплексов, которые создают независимые домены транскрипции. Основной целью настоящего исследования было изучение структуры белка Мос1(тс1§4) и его функциональных свойств в составе инсуляторного комплекса.

Заключение диссертации по теме «Биофизика», Мазур, Александр Михайлович

6. выводы.

1. Белок Mod(mdg4) в составе инсуляторного комплекса блокирует репрессионное действие хроматина и не нужен непосредственно для блокирования энхансеров.

2.Показано, что в белке Mod(mdg4) содержится второй домен, который, помимо BTB/POZ домена, приводит к димеризации белка. Продемонстрировано, что идентифицированный домен белка Mod(mdg4) необходим для эффективной гетеродимеризации с ВТВ-содержащим GAF белком.

3. Продемонстрировано, что ВТВ домен необходим для связывания белка Mod(mdg4) с Su(Hw) инсулятором. Замена ВТВ домена белка Mod(mdg4) на аналогичный из белка GAF приводит к потери взаимодействия химерного белка с Su(Hw) инсулятором in vivo и неспособности образовывать ядерные тельца, которые характерны для нормального белка Mod(mdg4).

4. Функциональность ВТВ домена в работе инсулятора во многом определяется суммарным зарядом, а не структурными особенностями наиболее консервативных аминокислот.

5. Глутамин-богатый домен необходим для транспорта ВТВ содержащих белков в ядро.

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