Бесплатный автореферат и диссертация по биологии на тему

Структурно-функциональная характеристика системы рестрикции-модификации ДНК CfrBI штамма Cirobacter freundii 4111

ВАК РФ 03.00.03, Молекулярная биология

Содержание диссертации, кандидата биологических наук, Белецкая, Ирина Викторовна

ВВЕДЕНИЕ.

I. ОБЗОР ЛИТЕРАТУРЫ.

1.1. Системы рестрикции-модификации.

1.1.1. Явление рестрикции-модификации.

1.1.2. Сайт-специфические эндонуклеазы и ДНК-метилтрансферазы.

1.1.3. Распространение систем рестрикции-модификации.

1.1.4. Молекулярная организация систем рестрикции-модификации.

1.1.5. Классификация ферментов системы рестрикции-модификации.

1.1.6. Системы рестрикции-модификации I типа.

1.1.7. Системы рестрикции-модификации 11/2 типа.

1.1.8. Системы рестрикции-модификации II типа.

1.1.9. Ферменты системы рестрикции-модификации III типа.

1.1.10. Ферменты системы рестрикции-модификации IV типа.

1.2. Непарные ДНК-метилтрансферазы и эндонуклеазы рестрикции.

1.3. Метилирование ДНК в E.coli.

1.3.1. Dam-зависимая регуляция генной экспрессии.

1.4. Метилирование ДНК эукариотических организмов.

1.4.1. Метилирование и процессы развития.

1.4.1.1. Импринтинг.

1.4.1.2. Инактивации хромосомы X.

1.4.2. Распределение CpG в геноме человека.

1.4.3. Влияние метилирования ДНК на структуру хроматина.

1.5. Регуляция экспрессии генов в системах Р-М.

1.5.2. Регуляция экспрессии генов Llal системы Р-М из Lactococcus lactus.

1.5.3. Регуляция экспрессии генов в системах Р-М II типа.

1.5.4. Регуляция экспрессии генов Р-М систем III типа.

II. МАТЕРИАЛЫ И МЕТОДЫ ИССЛЕДОВАНИЙ.

11.1. Материалы.

11.1.1. Штаммы бактерий, бактериофаги, фаговые и плазмидные вектора.

11.1.2. Среды и основные буферы.

11.1.3. Материалы и реактивы.

11.2. Методы исследования.

11.2.1. Выделение плазмидной ДНК.

11.2.1.1. Лизис щелочью.

11.2.1.2. Модифицированный метод лизис щелочью с последующей очисткой ДНК.

11.2.1.3. Лизис кипячением.

11.2.1.4. Очистка плазмидной ДНК равновесным центрифугированием в градиенте хлористого цезия.

11.2.2. Получение компетентных клеток Е. coli и их трансформация.

11.2.3. Полимеразная цепная реакция (ПНР).

11.2.4. Препаративное выделение фрагментов ДНК из легкоплавкой агарозы.

11.2.5. Препаративное выделение фрагментов ДНК из полиакриламидных гелей.

11.2.6. Получение препаратов фагов Xvir и q>80v/r в высоком титре.

11.2.7. Выделение ДНК фагов Ш857, Xvir и q>80v/r.

11.2.8. Определение ферментативной активности и специфичности R.C/rBI.

11.2.9. Определение точки разрезания фосфодиэфирной связи R.C/rBI на молекуле субстратной ДНК.

11.2.10. Клонирование гена эндонуклеазы R.C/rBI.

11.2.11. Клонирование гена ДНК-метилтрансферазы М CfrBL.

11.2.12. Экспрессия генов эндонуклеазы His6-R.CyrBI- и метилтрансферазы His6-M.QrBI.

11.2.13. Определение молекулярного веса белков R'C/rBI и M'CJrBI.

11.2.15. Определение оптимальных условий реакции для метилтрансферазы His6-C/rBI.

11.2.16. Реакция метилирования in vivo и in vitro.

11.2.17. Определение типа цитозинового метилирования, осуществляемое M.CfrBl.

II.2.18. Конструирование рекомбинантиых плазм ид с перекрывающимися уникальными сайтами для определения позиции метилированного цитозина в последовательности сайта CfrBl.

11.2.19. Конструирование плазмид, производных pFD51, содержащих различные варианты промоторных областей генов cfrBIR and cfrBIM.

11.2.20. Определение активности галактокиназы.

11.2.21. Определение связывания Ш.С/гШ с промоторной областью гена cfrBIM методом задержки в агарозном геле.

11.2.22. Транскрипция in vitro.

11.2.23. Определение нуклеотидной последовательности ДНК.

III. РЕЗУЛЬТАТЫ И ОБСУЖДЕНИЕ.

111.1. Характеристика генетической организации системы рестрикции-модификации CfrBl.

111.2. Сравнительный анализ аминокислотных последовательностей Ш.С/гШ и R.C/rBI с последовательностями других ферментов систем Р-М.

111.3. Определение сайта узнавания и места гидролиза фосфодиэфирной связи на молекулах субстратной ДНК R.C^rBI.

111.4. Определение типа метилирования цитозиновых остатков, осуществляемое Ш.С/гШ.

111.5. Создание штаммов-продуцентов с регулируемым уровнем экспрессии ферментов системы рестрикции-модификации CfrB1.

111.5.1. Клонирование и экспрессия гена cfrBIR.

111.5.2. Клонирование и экспрессия гена cfrBIM.

111.6. Очистка и определение оптимальных условий реакции для His6-M.C/>BI.

111.7. Определение локализации метилированного основания в последовательности сайта CfrBl.

111.8. Исследование регуляции экспрессии генов в системе рестрикции-модификации CfrBI.

111.8.1. Определение минимального района ДНК с функционально активным промотором гена cfrBIM.

111.8.2. Изучение регуляции генов cfrBIM и cfrBIR в системе in vivo.

111.8.3. Зависимость эффективности транскрипции с промоторов генов cfrBIR и cfrBIM от метилирования цитозинов в сайте CfrBl, расположенного в промоторной зоне этих генов.

111.8.4. Транскрипция in vitro с промоторов генов cfrBIR и cfrBIM.

111.8.5. Новый способ регуляции генной активности систем R-M.

ВЫВОДЫ.

Введение Диссертация по биологии, на тему "Структурно-функциональная характеристика системы рестрикции-модификации ДНК CfrBI штамма Cirobacter freundii 4111"

Системы рестрикции - модификации (Р-М) широко распространены среди различных микроорганизмов. К настоящему времени обнаружено и охарактеризовано свыше 3000 различных систем Р-М с более чем 200 специфичностями (Roberts and Macelis, 1998). Основная функция систем Р-М II типа, компонентами которой являются эндонуклеазы рестрикции (ЭР) и модифицирующие ДНК-метилтрансферазы (МТ), сводятся к защите бактериальной клетки-хозяина от проникновения чужеродной ДНК. Имеются также данные о том, что ферменты рестрикции и модификации могут оказывать влияние на такие важнейшие клеточные процессы, как репликация, транскрипция, транспозиция и рекомбинация.

ЭР и МТ широко используют в качестве инструментов в генно-инженерных работах при получении рекомбинантных ДНК в биологии, в медицине и в сельскохозяйственной биотехнологии. Это, в первую очередь, определяет актуальность прикладного аспекта изучения систем Р-М, заключающегося в поиске штаммов с новыми специфичностями, в получении высокоэффективных продуцентов ферментов.

Ферменты систем Р-М являются также привлекательной моделью для изучения белок-нуклеинового и белок-белкового взаимодействия, благодаря широкому разнообразию последовательностей узнаваемой ДНК, высокой специфичности ферментов и тому обстоятельству, что для многих из них известны аминокислотные последовательности и для более чем 15 белков сделан рентгеноструктурный анализ. В последнее время системы Р-М все больше привлекают исследователей с точки зрения изучения регуляции экспрессии генов. Продукты генов системы - МТ и ЭР - являются белками, составляющими защитную систему клетки, регуляция экспрессии их генов важна для выживания хозяйского организма. Основной смысл регуляции активностей генов в системах Р-М - предотвращение авторестрикции, т.е. клеточная ДНК должна быть полностью модифицирована к моменту появления эндонуклеазной активности. Поскольку многие гены систем Р-М локализованы на плазмидах, генная регуляция важна не только для предотвращения фрагментации ДНК хозяйского организма, но и для проникновения и установления системы Р-М в новой клетке-хозяине. Механизмы регуляции активности генов в системах Р-М различны и требуют детального изучения для каждой из систем. Объектом нашего исследования является система Р-М С/гШ, обнаруженная на природной плазмиде в штамме Citrobacter freundii 4111. Гены системы R-M CfrBl расположены дивергентно и их промоторные области в значительной степени перекрываются. Уникальный для всей последовательности генов сайт CfrBl локализован в межгенной области. Перекрывание промоторных областей генов и расположение уникального сайта CfrBl в этой области перекрывания делает эту систему привлекательной моделью для исследования регуляции экспрессии генов.

Настоящая диссертационная работа посвящена исследованию структурно-функциональной организации системы рестрикции-модификации CfrBl, характеристике специфичности ферментов, кодируемых генами этой системой, и изучению механизма регуляции экспрессии генов cfrBIM и cfrBIR. Исходя из этого, в работе последовательно решались следующие задачи:

1. Идентифицировать генетические детерминанты системы Р-М CfrBl, обнаруженной на природной плазмиде клинического штамма Citrobacter freundii.

2. Клонировать гены cfrBIM и cfrBIR и определить их нуклеотидные последовательности. Охарактеризовать генетическую организацию системы Р-М CfrBl.

3. Сконструировать штаммы с увеличенным синтезом ферментов системы, для получения высокоактивных и гомогенных препаратов МТ и ЭР.

4. Определить последовательность узнавания и место гидролиза фосфодиэфирной связи для R.C/rBI.

5. Определить тип модификации, осуществляемый M.C/rBI, и положение цитозинового основания в сайте CfrBl, подвергающегося метилированию.

6. Изучить механизм регуляции экспрессии генов системы Р-М CfrBl.

Работа выполнена в ВНТК "Генная активность" Института биохимии и физиологии микроорганизмов РАН.

I. ОБЗОР ЛИТЕРАТУРЫ

Заключение Диссертация по теме "Молекулярная биология", Белецкая, Ирина Викторовна

выводы

1. Определена первичная структура генов системы рестрикции-модификации CfrBl и установлено, что гены системы расположены дивергентно относительно друг друга. В области перекрывания промоторов генов cfrBIM и cfrBIR расположен уникальный для всей последовательности системы рестрикции-модификации сайт CfrBl.

2. Сконструированы штаммы-продуценты эндонуклеазы рестрикции CfrBl и ДНК-метилтрансферазы CfrBl. Разработана схема очистки гомогенного препарата фермента ДНК-метилтрансферазы CfrBl.

3. Определен сайт узнавания и место гидролиза фосфодиэфирной связи эндонуклеазы рестрикции CfrBl. Показано, что метилтрансфераза CfrBl относится к классу N4-цитозиновых метилтрансфераз и метилирует наружный цитозин в последовательности 5'-4mCCWWGG -3'.

4. Предложена и экспериментально подтверждена новая модель регуляции экспрессии генов систем рестрикции-модификации. Впервые показано участие N4mC остатков ДНК в регуляции экспрессии генов на уровне транскрипции.

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