Идентификация новых генов дрожжей S. pombe и их роль в рекомбинационной репарации ДНК тема диссертации и автореферата по ВАК РФ 03.01.07, доктор биологических наук Хасанов, Фуат Каримович

• Хасанов, Фуат Каримович
• доктор биологических наук
• 2011

Оглавление диссертации доктор биологических наук Хасанов, Фуат Каримович

СПИСОК СОКРАЩЕНИЙ.

ГЛАВА 1. ВВЕДЕНИЕ.

ГЛАВА 2.0Б30Р ЛИТЕРАТУРЫ.

2.1. Рекомбинационная репарация в б1. ротЬе: роль в поддержании целостности генома.

2.2. Преимущества делящихся дрожжей для изучения репарации двухцепочечных разрывов ДНК.

2.3. Гены рекомбинационной репарации & ротЬе.

2.3.1. Белки 51. ротЬе, ответственные за образование 3'- выступающих однонитевых участков в сайтах повреждений ДНК.

2.3.2. Белки, ответственные за образование 11ас151-нуклеопротеинового филамента.

2.4. Механизм рекомбинационной репарации в эукариотах.

2.5. 8Ш и толерантность к УФ - повреждениям ДНК.

2.6. Связь механизмов контроля клеточного цикла и репарации повреждений

ГЛАВА 3. МАТЕРИАЛЫ И МЕТОДЫ.

3.1. Штаммы, среды и ростовые условия.

3.2. Использованные библиотеки ДНК и плазмиды.

3.3. Конструирование делеции гена & pom.be гкр55+.

3.4. Конструирование делеционного штамма Б.ротЪе Нр1.

3.5. Обнаружение и клонирование & ротЬе

3.6. Конструирование делеционного мутанта & ротЬе з/г!А::а^З+.

3.7. Эксперимент с повышенной экспрессией белка БМ.

3.8. Выделение белка БАГ из клеток ротЬе.

3.9. Манипуляции с ДНК.

3.10. Тесты на клеточный ответ на генотоксический стресс.

3.11. Мейотический тайм-курс и Нозерн анализ.

3.12. Определение уровня образования двуцепочечных разрывов ДНК в локусе S. ротЪе matl.

3.13. Тесты на белок - белковые взаимодействия.

3.14. Конструирование слитого белка His6-Rhp55.

3.15. Конструирование аллелей rhp55K57A и -K57R, а также rhp57K106A и K106R в хромосоме S. ротЪе.

3.16. Конструирование аллелей sfrl-K108E и sfrl-K164E, а также sfrl-F107E и sfrl-F163E в хромосоме S. pombe.

3.17. Рекомбинационный эксперимент на митотических клетках.

3.18. Эффективность споруляции и жизнеспособность спор.

3.19. Тесты на определение уровней мейотической рекомбинации.

3.20. Цитология и проточная цитометрия.

3.21. Приготовление хроматиновых спредов.

3.22. Иммунофлуоресцентная микроскопия.

3.23. Тест на образование ДНК - белковых комплексов в агарозном геле.

ГЛАВА 4. РЕЗУЛЬТАТЫ ИСЛЕДОВАНИЯ.

4.1. rhp55 + кодирует новый белок S. pombe с гомологией к RecA.

4.2. rhp55+ транскрибируется в вегетативно растущих клетках и индуцируется в мейозе.

4.3. rhp55 + является геном репарации повреждений ДНК.

4.4. кДНК rhp55+ комплементирует дефект в репарации повреждений ДНК, вызванный мутацией rhp55A.

4.5. S. pombe Rhp55 функционирует в одном пути с белками Rad и Rhp54.

4.6. Клетки rhp55A содержат аберантные нуклеусы и показывают повышенное содержание ДНК.

4.7. Делеция гена S. pombe rhp55 приводит к нарушениям мейоза и вызывает небольшое снижение мейотической рекомбинации.

4.8. Rhp55 и Rhp57 взаимодействуют in vivo.

4.9. Мутации в Walker мотиве «А» белков Rhp55 и Rhp57 приводят к ослабленной репарации ДНК.

4.10. Эффект мутаций в доменах связывания/гидролиза АТФ на функцию комплекса Rhp55-Rhp57 в клеточной пролиферации.

4.11. Белки репарации двуцепочечных разрывов ДНК S. pombe вовлечены во взаимные взаимодействия.

4.12. Взаимодействия, включающие белки S. pombe Rad22, Rtil и Rpal.l

4.13. Штаммы h90 с делециями генов rhp51+ и rhp55+ показывают «крапчатый» фенотип и образуют гетероталличные сегреганты.

4.14. Дефект клеток мутанта с делецией гена rhp55+ в переключении типа спаривания возрастает при понижении температуры.

4.15. Анализ организации геномной области, ответственной за переключение типа спаривания в клетках сегрегантов.

4.16. Секвенирование области smt у сегрегантов h90 с делецией гена rhp55+ показывает присутствие перестроек ДНК.

4.17. Замещение последовательности ТТТССА на GTTTGTG в области SAS2 не коррелирует с низким уровнем образования разрывов ДНК в matl:l.

4.18. rlpl+ кодирует новый RecA-подобный белок S. pombe с высокой гомологией к белку человека XRCC2.

4.19. rlpl + является геном репарации повреждений ДНК, действующим в одном пути с rhp51+, rhp54+ и rhp55+

4.20. Rlpl не имеет роли в репарации УФ-повреждений и в ответе на репликационный стресс.

4.21. Спонтанная митотическая внутрихромосомная рекомбинация в мутанте rlpl.

4.22. Мейоз и переключение типа спаривания в мутанте rlpl.

4.23. Дрожжевой двугибридный анализ взаимодействий Rlpl с другими белками рекомбинационной репарации.

4.24. Дрожжевой двугибридный анализ взаимодействия Rlpl с мейотическим гомологом S.pombe.

4.25. Доминантно-негативный эффект повышенной экспрессии Rhp51 на чувствительность мутанта rlpl к метил метансульфонату.

4.26. Sfrl - высококопийный супрессор нарушения репарации клеток, лишенных S. ротЪе Rad51 паралогов, Rhp55 (Rad55Sp) и Rhp57 (Rad57Sp).

4.27. Sfrl является членом пути рекомбинационной репарации ДНК, который действует в новом Rad51-зависимом пути, параллельно Rad51 паралогам Rhp55-Rhp57 и Rlpl.

4.28. Sfrl не играет существенной роли в возобновлении остановленной репликации и в переключении типа спаривания.

4.29. Белок S. pombe Sfrl взаимодействует с рекомбиназой Rhp51.

4.30. Образование фокусов Rhp51, индуцированных ионизирующей радиацией, уменьшено в мутанте sfrl Л.

4.31. Синергичное взаимодействие sfrl с мутантами г ad50 и exol с нарушениями в процессинге двуцепочечных разрывов ДНК.

4.32. Эпистатический анализ sfrl с мутантами по ДНК-геликазам rqhl и srs2.

4.33. Взаимодействие Sfrl с белками S. pombe Radi 8 и Rad60.

4.34. Sfrl участвует в Cdsl-независимом пути толерантности к УФ повреждениям ДНК.

4.35. Sfrl не вовлечена в поддержание целостности хромосом и митотическую рекомбинацию.

4.36. Мейотическая рекомбинация уменьшена в мутанте sfrl А.

4.37. Sfrl является ядерным белком.

4.38. Белок S. pombe Sfrl взаимодействует с Rad51Sp^n,HHK филаментом in vitro.

4.39. Идентификация нового мотива в белке Sfrl и его анализ.

4.40. Повышенная экспрессия PSA повторов приводит к Rad51 ^-зависимому доминантно-негативному эффекту на выживаемость клеток.

4.41. Мутации в PSA мотивах белка Sfrl приводят к ослабленной репарации ДНК в клетках S. Pombe.

4.42. Мейотическая рекомбинация уменьшена в б/г1 РБА-мутантных аллелях.

4.43. 8М-мутантные аллели дефектны для взаимодействия с Ыас1518р.

ГЛАВА 5. ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ.

5.1. & ротЪе Ш1р55, гомолог 5". сегехпягае Кас155, является новым белком рекомбинационной репарации в клетках делящихся дрожжей.

5.2. Белки Ы1тр51, Шхр54 и Ш1р55 образуют одну эпистатическую группу рекомбинационной репарации.

5.3. Белок КЬр55 вовлечен в поддержание стабильности генома и мейоз.

5.4. Свойства гетеродимера Я. ротЪе Ш1р55-Штр57.

5.5. Роль белков рекомбинационной репарации в механизме переключения типа спаривания у дрожжей.

5.6. Возможная функция Шр1, нового 11ас1518р паралога, в клеточном ответе «£ ротЪе на повреждение ДНК.

5.7. Особенности 8М-8"м5 медиаторного пути и ее эволюционная консервативность в клетках эукариот.

5.8. ЯасШ-зависимые суб-пути рекомбинационной репарации в клетках делящихся дрожжей.

5.9. 8£г1 и толерантность к УФ повреждениям ДНК.

5.10. Функция повторов аминокислотной последовательности белка 8М в рекомбинационной репарации & ротЪе.

ВЫВОДЫ.

Заключение диссертации по теме «Молекулярная генетика», Хасанов, Фуат Каримович

выводы

1. Идентифицированы три новых гена, rhp55+, rlpl+ и sfrl+, в клетках дрожжей S. pombe с функцией в рекомбинационной репарации двуцепочечных разрывов ДНК, два из которых, rhp55+ и rlpl+, кодируют белки с гомологией к Е. coli RecA.

2. Охарактеризованы фенотипы мутантов по генам S. pombe rhp55+, rlpl+ и sfrl+ в репарации повреждений ДНК, мейозе и репликации ДНК.

3. Молекулярный анализ показывает образование стабильного комплекса между Rhp55 и другим RecA-подобным белком Rhp57 в клетках S. pombe in vivo. Мутации в сайтах связывания и гидролиза АТФ у белков Rhp55 и Rhp57 приводят к ослабленной репарации ДНК и нарушениям в клеточной пролиферации, что указывает на важность этих доменов в репарации ДНК.

4. Впервые установлено, что функции генов rhp51+ и rhp55+ важны для процесса переключения типа спаривания, как механизма «половой» дифференциации в клетках дрожжей.

5. Впервые выявлены взаимодействия между белками репарации двуцепочечных разрывов ДНК, образующих «репарасому» в клетках S. pombe.

6. Показан новый механизм сборки Rad51 — нуклеопротеинового филамента с участием белка Sfrl и действующий параллельно механизму, контролируемому Rhp51 паралогами, Rhp55-Rhp57 и Rlpl. Полученные данные позволяют рассматривать возможность многообразия механизмов медиаторных путей в клетках высших эукариот.

7. Показан новый путь в рекомбинационном механизме толерантности к УФ - повреждениям ДНК, контролируемый белком Sfrl.

8. Обнаружен новый домен (PSA повторы) в белке S. pombe Sfrl, ответственный за взаимодействие с ключевым рекомбинационным белком Rhp51. PSA повторы являются важной функциональной частью белка Sfrl. Замещение фенилаланина в коровых участках повторов приводит к строгому

234 ослаблению репарации ДНК и рекомбинации в мейозе, что указывает на важность химической природы этого аминокислотного участка.

9. Биоинформатический анализ позволил идентифицировать белки с потенциальными PSA повторами и в других эукариотических организмах, что предполагает консервативность этих доменов в низших эукариотах, в частности, в грибах.

10. Предложена модель полимеризации белка Rhp51 на одноцепочечной ДНК с участием медиаторного комплекса Sfrl-Swi5 в клетках делящихся дрожжей.

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