Действие алкилирующих агентов и ионизирующей радиации на клетки человека с наследственными нарушениями репарации ДНК тема диссертации и автореферата по ВАК РФ 03.00.25, кандидат биологических наук Спивак, Ирина Михайловна

• Спивак, Ирина Михайловна
• кандидат биологических наук
• 1998

Оглавление диссертации кандидат биологических наук Спивак, Ирина Михайловна

Введение

Глава 1. Обзор литературы. Генетические заболевания с первичными и вторичными дефектами репарации ДНК

1.1. Эксцизионная репарация нуклеотидов

1.2 .Пигментная ксеродерма

1.3. Трихотио дистрофия 3 О

1.4. Синдром Коккейна 37 1.5 .Репарация двунитевых разрывов ДНК

1.6.Атаксия-телеангиэктазия

1.7.Анемия Фанкони

1.8. Синдром Блюма

1.9.Прогерии

1.9.1.Синдром Вернера

1.9.2.Синдром Хатчинсона-Гилфорда

Глава 2. Материалы и методы.

2.1 .Клеточные культуры

2.2 .Получение диплоидных фибробластов

2.3 .Получение лимфобластоидных линий

2.4.Ведение клеток, их клонирование и изучение выжи- 105 ваемости

2.5. Получение липосом

2.6. Получение RecA-белка

2.7. Иммунологическое исследование ЯесА-белка

2.8. Метод щелочного раскручивания ДНК с последую- 107 щим разделением на колонках с гидроксилапатитом

2.9 Повреждающие воздействия на клетки

2.10. Статистическая обработка результатов.

Глава 3. Результаты и обсуждение

3.1. Репарация ДНК в клеточных штаммах, полученных от больных с различными наследственными заболеваниями после гамма-облучения и обработки ал котирующими агентами прямого действия - эпоксидами (этиле-ноксидом, пропиленоксидом и эпихлорогидрином)

3.2. Участие рекомбиназ в процессах репарации после 167 гамма-облучения.

3.3. Роль конформационного сосотояния хроматина в 178 процессах репарации ДНК после гамма-облучения.

Выводы

Введение диссертации (часть автореферата) на тему «Действие алкилирующих агентов и ионизирующей радиации на клетки человека с наследственными нарушениями репарации ДНК»

Изучение механизмов репарации ДНК представляет несомненный интерес для клеточной биологии. Только нормальное функционирование этих репарирующих систем обеспечивает устойчивость клеток к облучению и действию химических агентов (Жестяников, 1979), стабилизирует генетический аппарат клетки при его нормальном функционировании - репликации и рекомбинации, то есть способствует поддержанию генетической стабильности клетки и обеспечению ее жизнедеятельности. Повреждения, возникшие в структуре ДНК и не подвергшиеся процессу репарации, неизбежно приводят к нарушению в других системах клетки, для которых ДНК служит источником и хранителем информации.

Одним из перспективных подходов к изучению репарационных процессов в ДНК является исследование мутантов с нарушениями тех или иных этапов репарации - процесса достаточно сложного и многообразного, к тому же неравномерно изученного. Если основные генетические механизмы эксцизионной репарации ДНК уже поняты (Sanear, 1996), то процессы восстановления двунитевых разрывов и шире - репарации повреждений после гамма-облучения - остаются недостаточно ясными. Таким образом, изучение мутантов с нарушениями процессов репарации ДНК от повреждений после гамма-облучения, особенно у человека, открывает перспективы не только для расшифровки механизмов репарации ДНК в клетках человека, что является главной задачей этого исследования, но и помогает пониманию генетических основ канцерогенеза и старения. Это также важно для выяснения роли репарации ДНК в нормальной жизнедеятельности клетки.

Сейчас существует достаточно большое количество клеточных штаммов человека, для которых описана их повышенная чувствительность к ионизирующему облучению и радиомиметикам (Lehmann, 1996; Zdzienicka, 1995). Именно сравнительное их изучение позволило в последнее время достичь значительного прогресса в этой области. В коллекции нашей лаборатории находится некоторое количество подобных штаммов, и подробное их описание и введение в международный научный обиход представляется нам необходимым.

Эпоксиды являются алкилирующими агентами прямого действия, мутагенный эффект которых сильно варьирует в зависимости от объекта. Обширная сводка сравнительной токсичности различных эпоксидов была сделана Эренбергом и Хусейном еще в 1981 году (Ehrenberg and Hussain, 1981) и Гири в 1992 (Giri, 1992). Наиболее изученным из эпоксидов является этиленоксид (ЕЮ), его действие подробно описано в обзоре Деларко (Dellarco et al., 1990). Этиленоксид широко используется в химической промышленности и известен как агент, активно загрязняющий окружающую среду и возможный канцероген (см. обзоры у Kolman et al., 1986; Florak and Zielhius, 1990). В статье Нигрена с соавторами (Nygren et al., 1994) детально описано образование разрывов под действием этиленоксида в нормальных человеческих диплоидных фибробластах при использовании различных методов. Пропиленоксид (РО) и эпихлорогидрин (ЕСН) являются производными этиленоксида и, как и этиленоксид, широко используются в химической промышленности (подробный обзор см. Kolman and Dusinska, 1995). Известно, что ЕЮ способен вызывать мутации в ГГФРТ-локусе в нормальных фибробластах человека при небольших дозах

2.5-10 мМ/час (Kolman et al., 1992). Изучение действия эпоксидов на большой панели клеточных линий, как диплоидных неиммортализованных фибробластов, так и лимфобластоидных, имеет принципиальное значение для углубленного исследования механизмов их действия на клеточном уровне.

Для более глубокого изучения механизмов и белков, вовлеченных в репарацию ДНК после гамма-облучения были предприняты попытки влиять на репарационный ответ с помощью введения экзогенной рекомбиназы и предварительного изменения конформации хроматина облучением в малой дозе (1-5сГр).

ЦЕЛИ И ЗАДАЧИ ИССЛЕДОВАНИЯ

Дальнейшее изучение линии XP2SP, двойная чувствительность которой к УФ- и гамма-облучению была описана Михельсоном (Михельсон, 1981) для уточнения ее чувствительности не только к гамма-облучению, но и к радиомиметикам.

2.Исследование репарации после гамма-облучения и действия гаммамиметиков в клетках CS1SP, взятых от больной с синдромом Коккейна, так как данные о радио чувствительности на клеточном уровне при этом заболевании достаточно противоречивы.

3. Атаксия-телеангиэктазия - заболевание достаточно изученное и характеризующееся на клеточном уровне повышенной радио I чувствительностью (Jorgensen and Shiloh, 1996). Интересным является каждый отдельный описанный случай, так как клетки могут различаться по своей чувствительности. Таким образом, для уточнения особенностей именно нашего случая - AT2SP - было необходимо провести исследование чувствительности клеток этого штамма не только к гамма-облучению, но и к различным гамма-миметикам.

4.Подробное изучение чувствительности клеточного штамма PR3SP к гамма-облучению и действию радиомиметиков, так как влияние подобных агентов на репарцию в клетках больных прогерией изучено недостаточно. Было бы желательно уточнить, относится ли наша больная прогерией к синдрому Вернера, или это какая-либо другая форма прогерии взрослых.

5.Изучение влияние иммортализации на репарацию ДНК от однонитевых разрывов, так как для двух больных - пигментной ксеродермой и прогерией взрослых - нами были получены лимфобластоидные клеточные линии, иммортализованные вирусом Эпштейн-Барра (Михельсон и др., 1993; Наседкина и др., 1997), которые мы использовали для сравнительного изучения репарации в "смертных" и "бессмертных" клеточных линиях.

6.Изучение возможность влиять на репарацию в клетках человека после гамма-облучения с помощью введения в облученные клетки экзогенной рекомбиназы - Ree А белка E.coli для исследования участия рекомбинации в ликвидации однонитевых и двунитевых разрывов ДНК.

7.Исследование роли конформационного состояния ДНК для репарации повреждений, то есть возможную вовлеченность в этот процесс геликазной активности в клетках, на модели, разработанной совместно с Беляевым (Belyaev et al., 1996), включающей предварительное гамма-облучение диплоидных фибробластов человека малой дозой.

НАУЧНАЯ НОВИЗНА ПОЛУЧЕННЫХ РЕЗУЛЬТАТОВ

Полученные нами результаты окончательно подтвердили повышенную радио чувствительность клеток больной пигментной ксеродермой, как диплоидных фибробластов XP2SP, так и лимфобластоидных XP2SP(L). Причем показана повышенная чувствительность этих клеток как по критерию выживаемости (XP2SP), образования однонитевых разрывов (XP2SP(L)) и их ликвидации (и диплоидные фибробласты и лимфобластоидные клетки).

Показано, что изученные нами дефекты репарации не связаны с иммортализацией клеток.

Новыми являются сведения о повышенной чувствительности клеток CS1SP к ионизирующему облучению и действию эпоксидов. Особенно интересными оказались данные об их пониженной способности (по сравнению со всеми остальными изученными линиями) ликвидировать однонитевые разрывы ДНК, образующиеся после действия пропиленоксида, эпоксида, связывающегося с ДНК наименее прочно. Эти данные заслуживают отдельного обсуждения.

Подробно описана репарация в клеточной линии AT2SP, которая по своей чувствительности к гамма-облучению и действию эпоксидов с достаточными на то основаниями отнесена к группе АТ-вариант (ссылка).

Изучение репарации в клетках PR3SP впервые показало их повышенную чувствительность к гамма-облучению и действию эпоксидов. Причем эта повышенная чувствительность была описана и в диплоидных фибробластах PR3SP и в лимфобластоидных иммортализованных клетках PR3SP(L). Повышенная чувствительность к гамма-облучению и двум из изученных эпоксидов мы наблюдали только по критерию выживаемости клеток. Но после действия этиленоксида ни те ни другие клетки не способны ликвидировать однонитевые разрывы, образующиеся в ДНК, причем со временем количество разрывов может даже возрастать (в лимфобластоидных клетках), а не уменьшаться. То есть этот дефект репарации ДНК от разрывов не может быть скорректирован иммортализацией клеток.

Впервые было показано, что RecA белок бактерии E.coli способен при введении в клетки человека с помощью липосом участвовать в процессах репарации ДНК после гамма-облучения (Spivak et al., 1991; Спивак и др., 1991). Таким образом была подтверждена роль рекомбинации в этих процессах - в ликвидации как однонитевых, так и двунитевых разрывов.

Показано, что изменение конформации хроматина при облучении клеток влияет на их выживаемость. Причем показано, что эта зависимость носит неоднозначный характер, а является циклической и зависит как от типа клеток, так и от дозы облучения.

ПРАКТИЧЕСКАЯ ЦЕННОСТЬ РАБОТЫ

Полученные в работе экспериментальные результаты расширяют и углубляют представления о характере и отчасти о механизмах действия ионизирующего облучения и радиомиметиков-эпоксидов на клетки человека и закономерностей репарации поврежденных клеток на уровне ДНК. Показана решающая роль процессов репарации в ликвидации разрывов ДНК после облучения и обработки эпоксидами.

Результаты работы существенны также для понимания генетических основ канцерогенеза и старения. В частности, полученные данные о том, что дефекты репарации в клетках от больной Р1138Р, имеющей признаки преждевременного старения, не комплементируются иммортализацией этих клеток. При трансформации только снимается ограничение пролиферации (лимит Хейфлика), характерное для ^трансформированных клеток, но это происходит в любых клеточных штаммах, а не только прогерийных. Таким образом можно предположить, что даже при снятии эффекта ограниченности делений клеточной популяции, мы не уберем другие признаки старения клеток, и подобный путь не является панацеей для человечества.

Эпоксиды - опасные поллютанты и это еще раз подтверждено на клеточной модели, содержащей несколько разных штаммов клеток от больных с различными дефектами репарации ДНК. С методической точки зрения использование подобного набора клеточных штаммов может служить удобной и незаменимой моделью для испытания других химических агентов на канцерогенность и мутагенность.

Подробное описание клеточных штаммов, полученных от больных в России, может быть в дальнейшем использовано для создания банка данных о мутациях, распространенных в нашей стране и их сравнения с ранее описанными. Это важно для понимания этиологии данных заболеваний и возможных перспектив генной терапии.

АПРОБАЦИЯ РАБОТЫ

Материалы работы были представлены на XVII Генетическом конгрессе в 1993 году в Бирмингеме (Англия), в 1994 году на I съезде ВОГИС в Саратове и на 3-ей конференции Европейского общества аналитических исследований клеточной патологии в Гренобле (Франция), в 1995 году на ежегодной встрече токсикологов Северной Европы в 1995 году в Тампере (Финляндия), в 1996 году на 9-ом международном конгрессе по генетике человека в Рио-де-Жанейро (Бразилия), а также были неоднократно обсуждены на научных семинарах института цитологии РАН и департамента радиобиологии Стокгольмского Университета.

Заключение диссертации по теме «Гистология, цитология, клеточная биология», Спивак, Ирина Михайловна

выводы.

1.Показана повышенная чувствительность линии XP2SP к радиомиметикам - эпоксидам и подтверждена повышенная чувствительность к ионизирующей радиации по критериям выживаемости и ликвидации однонитевых разрывов ДНК.

2.Показана повышенная чувствительность линии CS1SP к ионизирующему облучению и действию эпоксидов, особенно пропиленоксиду, что отличает ее от других линий.

3.Показана пониженная выживаемость клеток линии PR3SP при действии ионизирующей радиации и эпоксидов. Особенно резко повышена чувствительность клеток к этиленоксиду, в первую очередь по критерию ликвидации однонитевых разрывов ДНК. В то же время репарация ДНК от однонитевых разрывов после гамма-облучения не нарушена.

4.Показана повышенная чувствительность линии AT2SP к действию алкилирующих агентов - эпоксидов, особенно этиленоксида.

5.Показано, что по критериям выживаемости и ликвидации однонитевых разрывов после ионизирующего облучения линия AT2SP относиться к АТ-вариант.

6.Лимфобластоидные линии, полученные от тех же больных, что и диплоидные фибробласты, более чувствительными к действию повреждающих агентов.

7.Пониженная репарация ДНК в клетках человека после гамма-облучения может быть скорректирована введением экзогенной рекомбиназы - RecA белка Escherihia coli.

8.Процесс репарации ДНК после гамма-облучения зависит от того, какова коиформация хроматина в момент облучения, причем эта зависимость не является однозначной, а носит циклический характер.

ЗАКЛЮЧЕНИЕ

В заключение я хочу выразить глубокую благодарность моим руководителям - профессору В.М. Михельсону и доценту Стокгольмского Университета Dr.Ade Колъман, без помощи и участия которых эта работа не была бы осуществлена.

Выражаю сердечную признательность сотрудникам Лаборатории радиационной цитологии за дружеское участие, доброжелательное отношение и обсуждение результатов работы.

Я искренне благодарна Отделу радиационной биологии Стокгольмского Университета, на базе которого была выполнена большая часть этого исследования, и всем его сотрудникам за помощь и прекрасное отношение ко мне во время моей работы в Швеции.

Большое спасибо Шведскому Институту радиационной защиты (iSwedish Radioprolection Institute), предоставившему грант на эти исследования.

Хочу отдельно поблагодарить профессоров В.Д.Жестяникова, Л.Эренберга и К.Арлетта за полезные советы при обсуждении результатов работы.

Список литературы диссертационного исследования кандидат биологических наук Спивак, Ирина Михайловна, 1998 год

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