Релокализация генов-партнеров по незаконной рекомбинации в условиях ингибирования ДНК-топоизомеразы II тема диссертации и автореферата по ВАК РФ 03.00.03, кандидат биологических наук Рубцов, Михаил Александрович

• Рубцов, Михаил Александрович
• кандидат биологических наук
• 2009

Оглавление диссертации кандидат биологических наук Рубцов, Михаил Александрович

список сокращений. введение. i. обзор литературы.

1.1. Хромосомные транслокации, ассоциированные с онкологическими заболеваниями.

1.1.1. Незаконная рекомбинация.

1.1.2. История изучения механизмов незаконной рекомбинации.

1.1.3. Хромосомные транслокации и ассоциированные с ними заболевания.

1.1.4. Семейства химерных белков.

1.1.5. Гены-партнеры по хромосомным транслокациям и кластеризация точек разрыва ДНК.

1.1.6. Механизм возникновения хромосомных транслокаций.

1.1.7. Структура кластеров точек разрыва ДНК как предпосылка для образования хромосомных транслокаций.

1.2. двухцепочечные разрывы ДНК и их репарация.

1.2.1. Репарация двухцепочечных разрывов ДНК.

1.2.1. ДНК-топоизомераза II и ее функции в клетке.

1.2.2. Ингибирование ДНК-топоизомеразы II как причина образования двухцепочечных разрывов ДНК.

1.2.3. Ингибирование ДНК-топоизомеразы II как предпосылка для возникновения хромосомных транслокаций.

1.2.4. Гипотезы возникновения хромосомных транслокаций.

1.3. позиционирование хромосом в ядре и вероятность возникновения хромосомных транслокаций.

1.3.1. Хромосомные территории.

1.3.2. Пространственная близость хромосомных территорий способствует образованию транслокаций.

1.3.3. Перемешивание хромосомных территорий.

1.3.4. Современная модель организации хромосомных территорий.

1.3.5. Релокализация геномных локусов внутри ядра. Роль ядерных моторных белков в этих процессах. постановка задачи и методические подходы. ii. материалы и методы.

II. 1. Материалы.

II. 1.1. Клеточные линии.

II. 1.2. Антитела.

II. 1.3. Химические реактивы.

II. 1.4. Программное обеспечение.

II.2. Методы.

11.2.1. Культивирование клеточных линий.

11.2.2. Электрофорез в пульсирующем поле.

11.2.3. Определение количества мертвых клеток.

11.2.4. Иммуноокрашивание.

11.2.5. Флюоресцентная гибридизация in situ (FISH).

11.2.5.1. Приготовление двумерных препаратов фиксированных клеток.

11.2.5.2. Выделение бакмидной ДНК из клеток E.coli.

11.2.5.3. Синтез пробы.

11.2.5.4. Гибридизация.

11.2.5.5. Приготовление трехмерных препаратов клеток Jurkat.

11.2.5.6. Гибридизация с пробой Vysis.

11.2.6. Компьютерная обработка изображений.

11.2.7. Статистический анализ данных.

11.2.8. Иммунопреципитация хроматина.

11.2.8.1. Растворы.

11.2.8.2. Методика.

11.2.8.3. ПЦР в реальном времени с ТадМап-пробами. iii. результаты исследований.

III. 1. Анализ взаимного расположения генов АМН и ЕТО в культуре первичных эмбриональных фибробластов человека.

111.2. ингибирование лигирующей активности ДНК-топоизомеразы И вызывает перемещение гена ЕТО в направлении центра ядра.

111.3. ингибирование ДНК-топоизомеразы ii вызывает релокализацию гена ЕТО в область ядрышка.

111.4. ингибирование днк-топоизомеразы ii приводит к предпочтительному связыванию нуклеолина с bcr2 гена ЕТО. обсуждение результатов. выводы.

Введение диссертации (часть автореферата) на тему «Релокализация генов-партнеров по незаконной рекомбинации в условиях ингибирования ДНК-топоизомеразы II»

Лейкемии составляют 3% от общего числа всех онкологических заболеваний в мире. Четырьмя основными типами лейкемий являются острая лимфоцитарная лейкемия (ALL), хроническая лимфоцитарная лейкемия (CLL), острая мпелоидная ле11кемия (AML) п хроническая миелоидная лейкемия (CML). Развитие острой мпелоидной лейкемии обычно связывают с хролюсомнымн перестройками, приводящими к возникновению химерных генов. Транслокация t(8;21)(q22;q22), объединяющая гены АМЫ и ЕТО, известна как одна из наиболее частых хромосомных транслокаций, наблюдаемых при острой мпелоидной лейкемии. Ежегодно она диагносцируется в 40% случаев AML типа М2 (острая миелобластная лейкемия), а также сопровождает до 40% случаев детской AML, и вероятность ее возникновения практически не зависит от пола ребенка (Huret, 1997). Но особенно часто эта транслокация наблюдается при так называелнлх «обусловленных лечением» (treatment related) или вторичных лейкозах (t-AML).Исследования последних лет свидетельствуют о том, что во многих случаях к развитию вторичных лейкозов приводит противораковая химиотерапия «первичных» онкологических заболеваний, проводящаяся с использованием препаратов, специфически ингибирующих фермент ДНК-топоизомеразу П. ДНК-топоизомераза II является жизненно необходимым ферментом, так как катализирует топологические изменения в ДНК в ходе множества клеточных процессов, таких как сегрегация дочерних хромосом после завершения процесса репликации ДНК, транскрипция, рекомбинация и реорганизация хроматина. Именно поэтому при терапии онкологических заболеваний применяются препараты, ингибирующие ее активность и вызывающие гибель активно делящихся клеток. Вследствие сказанного представляется важным изучение механизмов возникновения хромосомных перестроек, возникающих вследствие ингибирования ДНК-топоизомеразы П. Знание этих механизмов должно не только внести существенный вклад в представления об организации и ф}Ч1кционпровании клеточного ядра, но и показать исследователям новые пути решения проблемы вторичных лейкозов.

Заключение диссертации по теме «Молекулярная биология», Рубцов, Михаил Александрович

1. Установлено, что в подавляющей части клеток, присутствующих в популяции первичных эмбриональных фибробластов человека (HEF 1698), гены AML1 и ЕТО сближены, но находятся в разных ядерных слоях.2. Продемонстрировано, что обработка клеток ингибиторами ДНК-топоизомеразы II приводит к перемещению внутри ядра гена ЕТО, в результате чего этот ген оказывается в одном ядерном слое с геном AML1, являющимся партнером гена ЕТО по хромосомным перестройкам.3. Показано, что обработка первичных эмбриональных фибробластов человека (HEF 1698) и клеток Jurkat этопозидом приводит к увеличению частоты ко локализации гена ЕТО с ядрышком.4. Продемонстрировано, что ингибирование ДНК-топоизомеразы II этопозидом в клетках Jurkat приводит к предпочтительному связыванию нуклеолина с Ьсг2 гена

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