|
ИСТИНА |
Войти в систему Регистрация |
ИПМех РАН |
||
RNA Splicing Increases Vulnerability of Cells to DNA-PK Inhibitorsстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или Scopus- Авторы: Kovina AP, Luzhin AV, Tatarskiy VV, Deriglazov DA, Petrova NV, Petrova NV, Kondratyeva LG, Kantidze OL, Razin SV, Velichko AK
- Журнал: International Journal of Molecular Sciences
- Том: 25
- Номер: 21
- Год издания: 2024
- Издательство: MDPI
- Местоположение издательства: Basel, Switzerland
- Первая страница: 11810
- DOI: 10.3390/ijms252111810
- Аннотация: DNA-dependent protein kinase (DNA-PK) is a key effector of non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair. Since its identification, a substantial body of evidence has demonstrated that DNA-PK is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis in cancer patients. Recent studies have also uncovered novel functions of DNA-PK, shifting the paradigm of the role of DNA-PK in oncogenesis and renewing interest in targeting DNA-PK for cancer therapy. To gain genetic insight into the cellular pathways requiring DNA-PK activity, we used a CRISPR/Cas9 screen to identify genes in which defects cause hypersensitivity to DNA-PK inhibitors. We identified over one hundred genes involved in DNA replication, cell cycle regulation, and RNA processing that promoted cell survival when DNA-PK kinase activity was suppressed. This gene set will be useful for characterizing novel biological processes that require DNA-PK activity and identifying predictive biomarkers of response to DNA-PK inhibition in the clinic. We also validated several genes from this set and reported previously undescribed genes that modulate the response to DNA-PK inhibitors. In particular, we found that compromising the mRNA splicing pathway led to marked hypersensitivity to DNA-PK inhibition, providing a possible rationale for the combined use of splicing inhibitors and DNA-PK inhibitors for cancer therapy.
- Добавил в систему: Разин Сергей Владимирович