Изучение роли белка Sgf11 в транскрипции и экспорте мРНК из ядра тема диссертации и автореферата по ВАК РФ 03.01.03, кандидат биологических наук Гурский, Дмитрий Ярославович

• Гурский, Дмитрий Ярославович
• кандидат биологических наук
• 2013

Оглавление диссертации кандидат биологических наук Гурский, Дмитрий Ярославович

СОДЕРЖАНИЕ.

СПИСОК СОКРАЩЕНИЙ.

ВВЕДЕНИЕ.

ОБЗОР ЛИТЕРАТУРЫ.

1. Общие механизмы транскрипции.

1.1. Приближенная общая схема транскрипционного цикла.

2. Комплексы, изменяющие структуру хроматина.

2.1. Комплексы АТФ-зависимого ремоделинга хроматина.

2.2. Связь комплексов ремоделинга хроматина.

2.3. Комплексы, химически модифицирующие хроматин.

2.4. Динамическая система модификаций белков, сопровождающих транскрипционнный цикл.

2.5. Гистонацетилтрансферазы. SAGA - подобные комплексы.

2.5.1. Комплексы Gcn5/PCAF. Структура белков семейства Gcn5 и PCAF.

2.5.2. Фракции весом 2MDa.

2.5.3. Фракции весом 0.7 MDa. АТАС - комплекс.

2.5.4. Функции гистонацетилтрансферазных Gcn5/PCAF комплексов.

3. Гнстонацстилтрансферазнын комплекс SAGA. Роль в процессе биогенеза мРНП частиц.

3.1. Активационные модули SAGA. НАТ-модуль. Роль в инициации и элонгации транскрипции.

3.2. DUB-модуль SAGA и его роль в инициации и элонгации транскрипции.

3.3. Связь модулей SAGA в процессе транскрипции.

4. Транскрипция и экспорт мРНП частиц.

4.1. Комплекс белков, связывающих Кэп (СВС).

4.2. От транскрипции к экспорту. THO/TREX комплекс.

4.3. Компоненты мРНП частиц, связывающие процессинг и экспорт.

4.4. Хеликаза Sub2p/UAP56.

4.5. Адапторы и рецепторы экспорта мРНП. Связь с транскрипцией.

4.5.1 Фактор экспорта Mex67-Mtr2/TAP-pl5.

4.5.2. Yralp.

4.5.3. SR-белки.

4.6. Позиционирование генов к ядерной поре и экспорт.

4.6.1. Нуклеопорины и комплекс ядерной поры.

4.6.2. TREX-2/AMEX комплекс. Позиционирование генов к ядерной поре.

ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ.

ОБЪЕКТ И ЗАДАЧИ ИССЛЕДОВАНИЯ.

МАТЕРИАЛЫ И МЕТОДЫ.

1. Материалы.

1.1. Программное обеспечение, базы данных.

1.2. Штаммы и вектора Е. coli.

1.3. Эукариотические клеточные линии и вектора, использованные в работе.

1.4. Среды для культивирования клеток.

1.5. Приборы и реактивы.

1.6. Линии i), melanogasíer.

1.7. Ферменты.

1.8. Антитела.

1.9. Праймерные олигонуклеотиды.

1.10. Генно-инженерные конструкции.

2. Методы.

2.1. Работа с ДНК.

2.1.1. Приготовление компетентных клеток.

2.1.2. Лигировсише.

2.1.3. Трансформация бактерий.

2.1.4. Выделение тазмидной ДНК (мшшпреп, щелочной лизис).

2.1.5. Обработка ДНКрестриктазами.

2.1.6. Гель-электрофорез ДНК и очистка ДНК.

2.1.7. ПЦР.

2.1.8. Секвенирование ДНК.

2.1.9. Трансформация S2 клеток.

2.1.10. Выделение геномной ДНК из мух и из культуры клеток.

2.2. Работа с РНК.

2.2.1. Выделение РНК.

2.2.2. ОТ-ПЦР.

2.2.3. Получение двуцепочечной РНК.

2.2.4. РНК-интерференция.

2.3. Гибридизация in situ.

2.3.1. РНК in situ гибридизация с СуЗ-oligo-dTпраймером.

2.3.2. РНК in situ гибридизация с ДНК-зондом к индивидуальному гену.

2.4. Работа с белками.

2.4.1. Экспрессия и очисткарекомбинантных белков.

2.4.3. Экспрессия рекомбинантных белков в S2-¡aiemKax.

2.4.3. Получение антител.

2.4.4. Очистка антител.

2.4.5. Белковый гель-электрофорез.

2.4.6. Вестерн-блот анализ.

2.4.7. Разведение популяции, сбор эмбрионов D. melanogasíer. Выделение эмбрионального ядерного экстракта и белковых экстрактов из культуры эукариотических клеток.

2.4.8. Хроматография и фракционирование эмбрионального экстракта.

2.5. Иммуноокрашивание.

2.5.1. Иммуноокрашивание S2 клеток.

2.5.2. Иммуноокрашивание иолшпенных хромосом.

2.6. Иммунопреципитация.

2.9.1. Иммунопреципитация белков из ядерного эмбрионального экстракта.

2.9.2. Иммунопреципитация белков из клеточного лизата.

2.9.3. Иммунопреципитация хроматина (СЫР).

2.9.4. Иммунопреципитация мРНП.

РЕЗУЛЬТАТЫ.

1. Изучение взаимодействия Sgfl 1 с компонентами SAGA DUBm.

2. Sgfl 1 привлекается в промоторную область гена hsp70 при активации транскрипции, и его привлечение зависит от РНК.

3. Sgfl 1 взаимодействует с мРНК индивидуальных генов и координирует общий экспорт мРНК.

4. Sgfl 1 присутствует в ядерной и цитоплазматической фракции 82-клеток, колокализуется с комплексом ядерной поры и взаимодействует с комплексом общего экспорта мРНК АМЕХ.

5. Sgfl 1 присутствует в составе нескольких комплексов, выделенных из ядерного экстракта эмбрионов дрозофилы, и ассоциирован с белком комплекса, связывающего 5'-Кэп.

6. СЬр80 необходим для привлечения Sgfl 1 в промоторную область гена hsp70.

ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ.

ВЫВОДЫ.

БЛАГОДАРНОСТИ.

Введение диссертации (часть автореферата) на тему «Изучение роли белка Sgf11 в транскрипции и экспорте мРНК из ядра»

Экспрессия генов является многостадийным процессом, включающим инициацию транскрипции, синтез мРНК, формирование мРНП частиц, их экспорт и трансляцию в цитоплазме. В эти процессы вовлечено большое количество различных факторов, однако механизмы сопряжения указанных этапов и взаимодействия факторов между собой остаются малоизученным. Ключевым этапом экспрессии генов является транскрипция. Транскрипция в современном понимании является совокупностью взаимосвязанных процессов, осуществляемых различными ферментативными системами и подверженных строгой многоуровневой регуляции.

Эукариотический геном характеризуется компактизацией ДНК в хроматин, который в настоящее время рассматривается как динамичная структура, принимающая участие в процессах транскрипции [1]. Для осуществления эффективной транскрипции структура хроматина должна быть изменена, или «ремоделирована». Системы, обеспечивающие изменения структуры хроматина, играют ключевую роль в регуляции экспрессии генов. Различные пути ремоделинга хроматина реализуются мультибелковыми комплексами, которые модифицируют структуру хроматина, обеспечивая факторам транскрипционного аппарата РНК - полимеразы II доступ к гену. Тонким инструментарием регуляции динамики нуклеосом является многочисленная система модификаций гистонов, осуществляемая в течение транскрипционного цикла различными многофункциональными комплексами ремоделинга хроматина [2].

Компартментализация эукариотической клетки (разделение на ядро и цитоплазму) ведет к пространственному разделению важнейших этапов экспрессии генов (таких, как транскрипция и трансляция) и обусловливает наличие процессинга мРНП частиц. В процессе созревания мРНП частица в ядре подвергается различным модификациям, включающим формирование Кэп - структуры на 5-конце мРНК, сплайсинг интронов (в большинстве случаев), созревание З'-конца мРНК и присоединение полиА-последовательности. В синтезе и контроле качества мРНП частиц задействована большая система белковых комплексов. Целый ряд регуляторных комплексов участвует в позиционировании активных генов к ядерной поре (Gene Gating). Сопряженный с синтезом и созреванием экспорт мРНП частиц осуществляется посредством белковых адаптеров, взаимодействующих с мРНК с одной стороны и ядерными рецепторами с другой и таким образом обеспечивающих перемещение мРНП частиц к комплексу ядерной поры (NPC). Комплекс ядерной поры вместе с аппаратом транскрипции также осуществляет регуляцию формирования мРНП частиц, обеспечивает ассоциацию эксирессируемых генов с ядерной порой и эффективный экспорт мРНП частиц в цитоплазму. Механизмы сопряжения процессов биогенеза и экспорта мРНП частиц в настоящее время активно изучаются.

Одним из механизмов, обеспечивающих связь процессов формирования и экспорта мРНП частиц, является полифункциональность многих компонентов аппарата экспрессии генов и их существование в составе различных белковых комплексов. Примером подобной мультифункциональности является описанный ранее в нашей лаборатории транскрипционный коактиватор ENY2, входящий в состав гистонацетилтрансферазного комплекса SAGA, комплекса элонгации транскрипции ТНО, комплекса экспорта мРНП частиц АМЕХ и других [3].

В настоящей работе впервые были охарактеризованы функции белка Sgfl 1 эукариот, изначально найденного как партнера ENY2 в дрожжевой двугибридной системе. Показано, что Sgfl 1 Drosohilci melanogaster вместе с белками ENY2 и Nonstop формируют субмодуль, интегрированный в DUBm комплекса SAGA. Показано, что Sgfl 1 ассоциирован с промотором SAGA-зависимого гена hsp70 в составе DUBm. Кроме того, Sgfl 1, не ассоциированный с DUBm, привлекается в промоторную область после активации транскрипции РНК-зависимо.

Впервые было показано, что Sgfl 1 участвует в экспорте тотальной мРНК из ядра в цитоплазму. Он взаимодействует как с мРНК гена hsp70, так и с мРНК других генов. В ядре Sgfl 1 колокализуется с ядерной порой и взаимодействует с комплексом экспорта мРНК АМЕХ.

Впервые были проанализированы комплексы, содержащие Sgfl 1, и был обнаружен новый комплекс, включающий Sgfl 1 и СЬр80, компонент комплекса СВС, связывающего Кэп-структуру на 5'-конце мРНК. Было показано, что взаимодействие Sgfll и СЬр80 существенно для участия Sgfl 1 в активации транскрипции hsp70.

На основании полученных результатов была предложена модель, определяющая роль многофункционального белка Sgfl 1 в транскрипции и экспорте мРНП частиц.

ОБЗОР ЛИТЕРАТУРЫ

Заключение диссертации по теме «Молекулярная биология», Гурский, Дмитрий Ярославович

выводы

1. Показано существование DUBm у D. melanogaster, содержащего белки Sgfl 1, ENY2 и Nonstop и ассоциированного с транскрипционным комплексом SAGA.

2. Установлено, что транскрипционный фактор Sgfll ассоциирован с промотором гена hsp70 в составе DUBm. В то же время Sgfl 1, не входящий в DUBm, привлекается на ген РНК-зависимо после активации транскрипции.

3. Выявлено, что Sgfll необходим для общего экспорта мРНК из ядра и взаимодействует с мРНК различных генов.

4. Показано, что Sgfll присутствует в ядре и цитоплазме клетки, колокализуется с комплексом ядерной поры и взаимодействует с комплексом общего экспорта мРНК АМЕХ.

5. Очищен новый белковый комплекс, в составе которого Sgfll взаимодействует с СЬр80, белком комплекса, связывающего Кэп-структуру.

6. Показано, что СЬр80 необходим для привлечения Sgfll в промоторную область гена hsp70 при активации транскрипции. Привлечение СЬр80 на промотор, так же, как и привлечение Sgfl 1, зависит от вновь синтезированной РНК.

БЛАГОДАРНОСТИ

Автор выражает благодарность коллегами, без помощи которых данная работа не смогла бы появиться на свет. Среди них особо хочется отметить Орлову Анастасию, Шидловского Юлия, Набирочкину Елену и Краснова Алексея за плодотворную совместную работу, а также Воробьеву Надежду, Сошникову Наталью за помощь в работе, ценные советы по выполнению экспериментов и обсуждение результатов. Невозможна данная работа была бы и без чуткого мудрого руководства Дарьи Копытовой и Софии Георгиевой. Искреннюю благодарность автор выражает оппонентам и рецензентам данной работы. Отдельную благодарность автор выражает своей второй половине, родственникам и друзьям за материальную и духовную помощь в работе, а также всех, поддержавших автора словом и делом.

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