Роль белка HP1 в регуляции длины теломер у Drosophila melanogaster тема диссертации и автореферата по ВАК РФ 03.00.26, кандидат биологических наук Савицкий, Михаил Юрьевич

• Савицкий, Михаил Юрьевич
• кандидат биологических наук
• 2003

Оглавление диссертации кандидат биологических наук Савицкий, Михаил Юрьевич

1. ВВЕДЕНИЕ

2. ОБЗОР ЛИТЕРАТУРЫ

2.1. Теломеры: структурное разнообразие

2.2. Организация теломер у почкующихся дрожжей и млекопитающих

2.3. Альтернативные пути удлинения теломер

2.4. НеТ-А и TART элементы, особенности строения

2.5. Ретротранспозоны и их участие в построении теломер

2.6. Известные факторы, связанные с функциями теломер у Drosophila melanogaster

2.7. Теломеры локализуются на ядерной оболочке

2.8. Теломерный эффект положения у D.melanogaster

2.9. Эволюционные аспекты особенностей теломер D.melanogaster

2.9.1. Теломеры дрозофилы утеряли теломеразу

2.9.2. Происхождение субтеломерных повторов D.melanogaster

2.9.3. Теломераза и non-LTR ретротранспозоны

2.10. HP 1 - структурные особенности

2.11. HP 1 и регуляция транскрипции

2.12. Роль метилирования К9НЗ в хромосомной локализации НР

2.13. Белки НР1, Su(var)3-9 и Su(var)3-7 действуют в комплексе, образуя прицентромерный гетерохроматин

2.14. Теломеры дрозофилы и комплекс HPl/Su(var)3-9/Su(var)3

2.15. Белковые комплексы HP 1 /ORC/HOАР и HP 1/НОАР

2.15.1. Комплекс HP 1/ORC/HOАР инициирует сборку гетерохроматина

2.15.2. Особенности межбелковых взаимодействий в комплексе

HP 1/ORC/HO АР

2.15.3. Белок НОАР сильно изменчив у разных видов Drosophila

2.15.4. На теломерах D.melanogaster находится комплекс HP 1/НОАР

2.16. НР1 взаимодействует с белком Ки

2.17. HP 1 взаимодействует с LBR 57 2.1В. Белок RB взаимодействует с НР

2.19. Белок RB вовлечен в контроль длины телом ер у млекопитающих

2.20. Фосфорилирование НР

3. МАТЕРИАЛЫ И МЕТОДЫ

3.1. Генетические методы 63 3.1.1. Мутации и линии Drosophila melanogaster

3.2. Молекулярные методы

3.2.1. Выделение ДНК из дрозофилы

3.2.2. Саузерн-блот анализ 64 3.2.2.1. Рестрикция, электрофорез и мобилизация ДНК на мембрану

3.2.2.2. Гибридизация ДНК на мембране с радиоактивными зондами

3.2.3. Амплификация ДНК

3.2.4. Секвенирование плазмид и ПЦР продуктов

3.2.5. Работа с плазмидной ДНК

3.2.5.1. Трансформация бактериальных клеток плазмидами

3.2.5.2. Выделение ДНК плазмид методом щелочного лизиса 66 1 3.2.5.3. Выделение фрагментов ДНК из геля и очистка ДНК от продуктов ферментативных реакций

3.2.6. Выделение РНК из мух с протеиназой К

3.2.7. Электрофорез РНК и Нозерн-блот гибридизация

4. РЕЗУЛЬТАТЫ 69 4.1. На фоне мутаций Su(var)2-5 возрастает частота присоединений НеТ-А и

TART элементов к концу хромосомы с терминальной делецией

4.2. Скорость деградации концевых последовательностей не изменяется на фоне Su(var)2-5 мутаций

4.3. Возможные механизмы НеТ-А and TARТприсоединений к терминальным последовательностям тепа, yellow

4.4. Su(var)2-5 мутации не усиливают генную конверсию по матрице на гомологичной хромосоме

4.5. Линии D.melanogaster с Su(var)2-5 мутациями обычно содержат большое количество НеТ-А и TART элементов

4.6. Su(var)2-5 мутации активируют транскрипцию НеТ-А элементов

5. ОБУЖДЕНИЕ РЕЗУЛЬТАТОВ

5.1. Белок НР1 участвует в контроле длины теломер у Drosophila melanogaster

5.2. Мутации в гене Su(var)2-5 способствуют удлинению хромосомы разными способами

6. ВЫВОДЫ

Введение диссертации (часть автореферата) на тему «Роль белка HP1 в регуляции длины теломер у Drosophila melanogaster»

Теломеры - это нуклеопротеиновый комплекс, который находится на концах линейных хромосом. Линейные хромосомы в результате неполной репликации постоянно укорачиваются, кроме того, их концы, по сути, являются двуцепочечными разрывами, которые в норме должны подвергаться репарации. Таким образом, ключевые функции теломер заключаются в специфическом узнавании и защите терминальной ДНК от системы репарации, а также поддержании длины теломерных последовательностей, что обеспечивает стабильность хромосом и, следовательно, поддерживает целостность генома.

В большинстве случаев новые последовательности ДНК добавляются на конец хромосомы РНК-зависимым ферментом теломеразой, которая действует как обратная транскриптаза. Такие теломеры состоят из огромного числа коротких тандемных повторов. Для большинства эукариот обычны 5-8 нуклеотидные повторы, так, например, у позвоночных это T2AG3 гексамеры, а у насекомых -T2AG2 пентамеры. При нарушении функций теломеразы происходит укорачивание терминальных последовательностей хромосомы, нарушается работа теломерного комплекса, концы хромосом начинают узнаваться репарационной системой, появляется ряд других нарушений, что, в конечном счете, приводит к гибели клеток. В некоторых случаях клетки выживают благодаря включению альтернативного механизма удлинения теломер. В основе этого механизма лежат процессы рекомбинации и терминальной конверсии. Организмы, утерявшие по каким-либо причинам в процессе эволюции теломеразу, также используют рекомбинацию/конверсию для поддержания длины теломер. Теломеры этих организмов состоят из повторяющихся субъединиц, но, в отличие от коротких теломеразных повторов, они большего размера. Кроме того, они сильно отличаются в пределах систематически близких групп и даже на разных хромосомах одного вида. Например, теломеры комаров Anopheles gambae несут повторы из 800 нуклеотидов, a Chironomus pallidmttatus — из 340, причем на разных хромосомах находятся разные семейства этих последовательностей. Эти черты разделяют и субтеломерные повторы Drosophila melanogaster. Терминальные последовательности хромосом D. melanogaster составляют повторы НеТ-А и TART ретротранспозонов, которые перемещаются на конец хромосомы посредством обратной транскрипции либо в результате рекомбинации или конверсии.

Строение теломерных комплексов у организмов, имеющих теломеразо-зависимую регуляцию длины теломер, уже изучено достаточно детально. В тоже время известно только два белка, входящих в комплекс, кэпирующий концы хромосом D.melanogaster: НР1 (heterochromatin protein 1) и HOAP (HP1/ORC associated protein). Утверждение об их кэп-функции базируется на следующих фактах: белки НР1и НО АР находятся на концах хромосом, и мутации в генах, кодирующих эти белки, приводят к многочисленным спайкам между теломерами разных хромосом (Fanti et а1, 1998; Cenci et al, 2003). Помимо этого, недавно были локализованы два фактора, находящиеся на третьей хромосоме и влияющие на длину теломер. Эти, пока еще не определенные, гены получили названия Tel (Telomere elongation) (Siriaco et al, 2002) и Eft с) (Enchancer of telomere conversion) (Melnikova and Georgiev, 2002). Таким образом, до настоящего времени не было известно ни одного белка, вовлеченного в регуляцию длины теломер у D.melanogaster.

Известно, что хромосомы D.melanogaster с делегированными теломерными последовательностями, нормально передаются из поколения в поколение, если терминальная делеция не затрагивает функционально значимые гены. Этот факт не тривиален, поскольку концы хромосом, не имеющие специфических теломерных последовательностей, должны были бы подвергаться репарации, что, в конечном счете, привело бы к аресту клеточного цикла. Жизнеспособность хромосом с терминальными делециями означает, что на их конце присутствует белковый комплекс, узнающий конец хромосомы и защищающий его от системы репарации. Кстати, кэпирующая функция белков НР1 и НО АР подтверждается их наличием на концах терминальных делеций.

Ранее нами была разработана генетическая система, позволяющая оценивать частоту присоединений НеТ-А и TART элементов к концу хромосомы с терминальной делецией (Kahn et al, 2000). В основе этой системы лежит использование хромосомы с обрывом в гене yellow. Использование этой системы позволило прояснить роль белка НР1 в контроле длины теломер у D.melanogaster.

2. ОБЗОР ЛИТЕРАТУРЫ

Заключение диссертации по теме «Молекулярная генетика», Савицкий, Михаил Юрьевич

6. выводы

1. Впервые показано, что белок НР1 - негативный регулятор длины теломер у D.melanogaster. Мутации Su(var)2-5 увеличивают частоту присоединений НеТ-А и TART элементов к концу хромосомы с терминальной делецией.

2. Создана генетическая система на основе локуса yellow для определения коротких конверсионных трактов.

3. Установлено, что удлинение конца хромосомы на фоне мутаций Su(var)2-5 может происходить разными способами: транспозицией и рекомбинацией.

4. Показано, что НР1 репрессирует транскрипцию НеТ-А элементов.

5. Продемонстрировано, что линии D.melanogaster, несущие мутантные аллели Su(var)2-5, имеют длинные теломеры.

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