Пространственная организация ДНК в ядре и индуцированные ДНК-топоизомеразой II хромосомные перестройки

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Пространственная организация ДНК в ядре и индуцированные ДНК-топоизомеразой II хромосомные перестройки (реферат, курсовая, диплом, контрольная)

Содержание

СПИСОК СОКРАЩЕНИЙ
1. Обзор литературы
- 1. 1. Пространственная организация ДНК в ядре
  - 1. 1. 1. Уровни компактизации ДНК
  - 1. 1. 2. Доменная структура генома
    - 1. 1. 2. 1. Ядерный матрикс
    - 1. 1. 2. 2. Прикрепленная к ядерному матриксу ДНК
    - 1. 1. 2. 3. Функции ДНК ядерного матрикса
  - 1. 1. 3. Хромосомные территории
- 1. 2. Незаконная рекомбинация и хромосомные перестройки
  - 1. 2. 1. Двухчепочечные разрывы ДНК (ДЦР) и их репарация
  - 1. 2. 2. Кластеризация точек разрыва при транслокациях, ассоциированных с лейкозами
  - 1. 2. 3. Структура хроматина как причина кластеризации первичных точек разрыва
  - 1. 2. 4. Участие топоизомеразы II в незаконной рекомбинации
  - 1. 2. 5. Пространственная организация ядра способствует образованию определённых транслокаций
Постановка задачи и методические подходы
2. Материалы и методы
- 2. 1. Материалы
  - 2. 1. 1. Клеточные линии
  - 2. 1. 2. Антитела
  - 2. 1. 3. Химические реактивы
- 2. 2. Методы
  - 2. 2. 1. Культивирование человеческих клеток
  - 2. 2. 2. Электрофорез в пульсирующем поле
  - 2. 2. 3. Приготовление препаратов ядерных матриксов in situ
  - 2. 2. 4. Иммуноцитохимия
  - 2. 2. 5. Определение относительной представленности различных участков ДНК во фракции ДНК ядерного матрикса
  - 2. 2. 6. Метод остановки полимеразной цепной реакции (PCR-stop assay)
  - 2. 2. 7. Иммунопреципитация хроматина
    - 2. 2. 7. 1. Растворы
    - 2. 2. 7. 2. Методика
3. Результаты исследований
- 3. 1. Подавление активности ДНК-топоизомеразы II приводит к образованию двухцепочечных разрывов ДНК
  - 3. 1. 1. Обработка клеток этопозидом приводит к образованию ДЦР
  - 3. 1. 2. Количество ДЦР зависит от концентрации этопозида
  - 3. 1. 3. Индуцированные monollДЦР эффективно репарируются
- 3. 2. РОЛЬ ядерного матрикса в репарации ДЦР, индуцированных ДНК-топоизомеразой II
  - 3. 2. 1. Индуцированные этопозидом фокусы гистона уН2АХассоциированы с ядерным матриксом
  - 3. 2. 2. Участки кластеризации точек разрыва (bcr) ассоциированы с ядерным матриксом
- 3. 3. Негомологичное соединение концов ДНК, как механизм хромосомных перестроек, индуцированных ДНК-топоизомеразой II
  - 3. 3. 1. Цитологический подход
  - 3. 3. 2. Молекулярно-биологический подход
    - 3. 3. 2. 1. Выбор геномной модели
    - 3. 3. 2. 2. Контрольные эксперименты
    - 3. 3. 2. 3. Иммунопреципитация хроматина
4. Обсуждение результатов
Выводы

Уже достаточно давно в химиотерапии различных опухолей используются ингибиторы ДНК-топоизомеразы II, и нередки случаи, когда использование этих препаратов приводит к развитию вторичных лейкозов, в основе которых лежат те или иные хромосомные перестройки (Auxenfants et al., 1992; Super et al., 1993). Известно также, что обработка клеток высших эукариот ингибиторами топоизомеразы II (например, этопозидом или амсакрином) может приводить к возникновению таких перестроек, как делеции, инсерции и транслокации (Maraschin et al., 1990; Shibuya et al., 1994). Более того, показано, что топоизомераза II обладает межмолекулярной ДНК-лигазной активностью и может осуществлять незаконную рекомбинацию ДНК in vitro (Gale, 1992). Не менее важным нам представляется тот факт, что образование ковалентных комплексов топоизомеразы и ДНК, вызванное подавлением лигирующей активности топоизомеразы II, может приводить к запуску систем репарации двухцепочечных разрывов ДНК. В клетках эукариот существуют два основных пути репарации ДЦР: гомологичная рекомбинация, играющая большую роль в клетках низших эукариот, и негомологичное соединение концов ДНК (NHEJ, non-homologous end joining). Существует множество косвенных данных о том, что именно NHEJ является основным механизмом репарации ДЦР, индуцированных топоизомеразой II (Adachi et al., 2003; Adachi et al., 2004).

Известно, что транслокации, ассоциированные с развитием некоторых лейкозов, имеют характерную черту — точки разрыва сосредоточены в достаточно узких участках генома, названных кластерами точек разрыва (bcr, breakpoint cluster region). Во многих из этих участков обнаружены сайты гиперчувствительности к.

ДНКазе I и топоП. Ранее было показано, что основной мишенью ингибиторов топоизомеразы II является нерастворимая форма фермента, связанная с ядерным матриксом и взаимодействующая с участками прикрепления ДНК к матриксу. Исходя из представленных данных логично предположить, что связанная с ядерным матриксом топоизомераза может играть важную роль в запуске систем репарации ДЦР, в результате действия которых возможно появление различных транслокаций.

Настоящая работа посвящена определению и изучению механизма возникновения хромосомных перестроек, индуцированных ДНК-топоизомеразой II. Отдельное внимание уделяется роли ядерного матрикса в этом процессе.

1. Обзор литературы.

Выводы:

1. Продемонстрировано, что стабилизированные ингибиторами комплексы топоизомеразы II с ДНК конвертируются в клетке в двухцепочечные разрывы, которые узнаются системами мониторинга целостности ДНК.

2. Показано, что при подавлении лигирующей активности ДНК-топоизомеразы II разрывы вносятся предпочтительно в участки прикрепления ДНК к ядерному матриксу.

3. Продемонстрировано, что участок кластеризации хромосомных разрывов, присутствующий в гене AMLI, прикреплен к ядерному матриксу.

4. Впервые продемонстрировано, что репарация двухцепочечных разрывов, вносимых в ДНК топоизомеразой II, осуществляется преимущественно системой негомологичного соединения концов ДНК.

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