Novel Cellular Functions of ATR for Therapeutic Targeting: Embryogenesis to Tumorigenesis

Abstract

The DNA damage response (DDR) is recognized as having an important role in cancer growth and treatment. ATR (ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has shown significant therapeutic potential in cancer treatment. ATR inhibitors have shown anti-tumor effectiveness, not just as monotherapies but also in enhancing the effects of standard chemotherapy, radiation, and immunotherapy. The biological basis of ATR is examined in this review, as well as its functional significance in the development and therapy of cancer, and the justification for inhibiting this target as a therapeutic approach, including an assessment of the progress and status of previous decades’ development of effective and selective ATR inhibitors. The current applications of these inhibitors in preclinical and clinical investigations as single medicines or in combination with chemotherapy, radiation, and immunotherapy are also fully reviewed. This review concludes with some insights into the many concerns highlighted or identified with ATR inhibitors in both the preclinical and clinical contexts, as well as potential remedies proposed.

Link Between Cellular Senescence and Changes in The Number and Size of Phosphorylated Histone H2ax Foci in Irradiated Human Fibroblasts

“…Фокусы γH2AX часто используют в радиобиологии в качестве суррогатного маркера двунитевых разрывов (ДР) ДНК. При этом часто забывают о том, что фосфорилирование H2AX может осуществляться киназой АTR в ответ на коллапс репликативных вилок или появление фрагментов однонитевой ДНК во время эксцизионной репарации нуклеотидов [5]. Кроме того, важно помнить о том, что анализ фокусов γH2AX позволяет анализировать не сами повреждения ДНК, а локальное ремоделирование структуры хроматина в ответ на эти повреждения [6].…”