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Fig. 4 | Journal of Hematology & Oncology

Fig. 4

From: Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer

Fig. 4

Participation of ATR in maintenance of genome stability. DNA double strand breaks or replication stress induce an ATR protein response. ATR is recruited to regions of ssDNA replication protein A (RPA) through its partner, ATR-interacting protein (ATRIP). Subsequently, RAD9–RAD1-hus1 (9-1-1 complex) and DNA topoisomerase 2 binding protein 1 (TOPBP1) are incorporated, leading to ATR activation. ATR–ATRIP recruitment results in CHK1 activation. This process is mediated by Claspin, Timeless and Tipin, which form a complex at replication forks. In the event of large areas of DNA damage or no repair, the replication fork stops, origin suppression occurs and the cell cycle is stopped. ATR/CHK1 blockade prevents DNA damage-induced cell-cycle arrest, resulting in inappropriate entry into mitosis, chromosome aberrations, unequal partitioning of the genome, and apoptosis

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