Длина теломер и активность теломеразы как биологические маркеры для диагностики и прогноза патологических нарушений

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Аннотация

Исследование биологии теломер продолжает оставаться актуальной проблемой. В последние годы на основе анализа нескольких тысяч клинических образцов здоровых лиц показано, что длина теломер (ДТ) лейкоцитов периферической крови коррелирует с ДТ клеток внутренних органов человека и отражает их состояние, снижается при действии повреждающих факторов и может служить показателем состояния здоровья. Снижение ДТ приводит к остановке пролиферации и рассматривается как показатель репликативного старения пролиферирующих клеток, а снижение ДТ лейкоцитов периферической крови – как показатель старения организма. Новые данные фундаментальных исследований позволили сформулировать представления о роли CST–полимеразы альфа/праймазы в синтезе комплементарной С-цепи ДНК после завершения синтеза 3′-G-оверхэнга теломеразой при репликации теломер. Открытие теломерной РНК TERRA и её роли в регуляции активности теломеразы (АТ) и альтернативного удлинения теломер, а также возможности трансляции TERRA стало свидетельством сложной регуляции поддержания ДТ на эпигенетическом уровне. Анализ совокупности опубликованных данных позволяет заключить, что теломеры являются динамическими структурами, и что ДТ претерпевает существенные изменения под воздействием повреждающих факторов и определяется не просто хронологическим возрастом, а суммарным эффектом воздействия всех экзогенных и эндогенных повреждающих факторов в течение жизни. Наследуемое снижение ДТ, обусловленное появлением мутаций в генах белков, определяющих строение теломер и участвующих в репликации теломер, в первую очередь белков шелтеринового комплекса, комплекса CST и теломеразы, обнаружено при ряде генетически обусловленных заболеваний – теломеропатий. Определение ДТ и АТ имеет большое значение для диагностики теломеропатий и может быть полезно при диагностике рака, а определение ДТ – для мониторинга состояния здоровья, в том числе при действии ионизирующего излучения и факторов космического полёта, и для прогноза индивидуальной чувствительности к действию повреждающих факторов разной природы. Разработанные в настоящее время генетические технологии анализа ДТ и АТ доступны для использования в клинических и эпидемиологических исследованиях, активно применяются при диагностике теломеропатий и мониторинге состояния космонавтов и продолжают совершенствоваться.

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Е. Ю. Москалева

НИЦ «Курчатовский институт», Курчатовский комплекс НБИКС-природоподобных технологий

Автор, ответственный за переписку.
Email: Moskaleva_EY@nrcki.ru
Россия, 123182 Москва

А. И. Глухов

ФГАОУ ВО Первый МГМУ им. И.М. Сеченова Минздрава России (Сеченовский Университет); Московский государственный университет имени М.В. Ломоносова

Email: moskalevaey@mail.ru

кафедра биологической химии, биологический факультет

Россия, 119048 Москва; 119991 Москва

А. С. Жирник

НИЦ «Курчатовский институт», Курчатовский комплекс НБИКС-природоподобных технологий

Email: moskalevaey@mail.ru
Россия, 123182 Москва

О. В. Высоцкая

НИЦ «Курчатовский институт», Курчатовский комплекс НБИКС-природоподобных технологий

Email: moskalevaey@mail.ru
Россия, 123182 Москва

С. А. Воробьева

ФГАОУ ВО Первый МГМУ им. И.М. Сеченова Минздрава России (Сеченовский Университет)

Email: moskalevaey@mail.ru

кафедра биологической химии

Россия, 119048 Москва

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2. Рис. 1. Открытая структура теломер и структура теломер в форме Т-петли с образованием D-петли в области внедрения одноцепочечного G-оверхэнга (а), и пример стабилизации структуры теломер белками шелтеринового комплекса, связывающимися с двухцепочечной (TRF1 и TRF2) и одноцепочечной (POT1) теломерной ДНК (б). Белки шелтеринового комплекса покрывают всю теломеру. Согласно данным Griffith et al. [11] и de Lange [15]

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3. Рис. 2. Роль CST–Polα/Prim в синтезе ДНК концов теломер. Теломераза обеспечивает удлинение G-оверхэнга лидирующей цепи ДНК, CST–Polα/Prim достраивает комплементарную С-цепь отстающей и лидирующей цепи ДНК на концах теломер. Когда реплисома достигает конца теломер, синтез последнего фрагмента Оказаки начинается за >40 нуклеотидов (нт) от места расплетания двунитевой ДНК. Polδ и Polε – ДНК-полимеразы δ и ε соответственно. Согласно данным Cai и de Lange [46]

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4. Рис. 3. Функции теломеразы в клетке. Сокращения: TERT и TR – каталитическая субъединица и РНК-компонент теломеразы соответственно; TERР – белок, транскрибируемый с матрицы TR; TERRA (telomeric repeat containing RNA) – длинная некодирующая РНК с теломерными повторами 5`-UUAGGG-3′ на 3`-конце. Постоянство ДТ обеспечивает теломераза или путь ALT благодаря синтезу теломерной ДНК, что необходимо для формирования Т-петли и сохранности хромосом. Кроме того, защитными функциями обладают субъединицы теломеразы TERT и TR. TERT может мигрировать в митохондрии и повышать уровень антиоксидантной защиты и антиапоптотической активности в этих органеллах. TR может служить матрицей для синтеза белка TERР, который проявляет антиапоптотическую активность. TERRA снижает АТ и стимулирует путь ALT для поддержания ДТ

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5. Рис. 4. Механизмы снижения АТ и уменьшения ДТ в клетках при действии ионизирующего излучения и развитии окислительного стресса при некоторых патологических состояниях. Сокращения: АФК и АФА – активные формы кислорода и азота соответственно; 8-OxodG – 8-оксо-7,8-дигидро-2′-дезоксигуанозин; TERRA (telomeric repeat containing RNA) – длинная некодирующая РНК с теломерными повторами 5′-UUAGGG-3′ на 3′-конце; R-петли – гибридные молекулы РНК–ДНК, которые ТERRA может образовывать с богатой цитозином цепью ДНК теломер и вызывать смещение цепи ДНК теломер, содержащей повторы TTAGGG

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