Department of Radiation Oncology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, United States.
DNA Repair (Amst). 2019 Sep;81:102655. doi: 10.1016/j.dnarep.2019.102655. Epub 2019 Jul 8.
Mechanisms that limit origin firing are essential as the ˜50,000 origins that replicate the human genome in unperturbed cells are chosen from an excess of ˜500,000 licensed origins. Computational models of the spatiotemporal pattern of replication foci assume that origins fire stochastically with a domino-like progression that places later firing origins near recent fired origins. These stochastic models of origin firing require dormant origin signaling that inhibits origin firing and suppresses licensed origins for passive replication at a distance of ∼7-120 kbp around replication forks. ATR and CHK1 kinase inhibitors increase origin firing and increase origin density in unperturbed cells. Thus, basal ATR and CHK1 kinase-dependent dormant origin signaling inhibits origin firing and there appear to be two thresholds of ATR kinase signaling. A minority of ATR molecules are activated for ATR and CHK1 kinase-dependent dormant origin signaling and this is essential for DNA replication in unperturbed cells. A majority of ATR molecules are activated for ATR and CHK1 kinase-dependent checkpoint signaling in cells treated with DNA damaging agents that target replication forks. Since ATR and CHK1 kinase inhibitors increase origin firing and this is associated with fork stalling and extensive regions of single-stranded DNA, they are DNA damaging agents. Accordingly, the sequence of administration of ATR and CHK1 kinase inhibitors and DNA damaging agents may impact the DNA damage induced by the combination and the efficacy of cell killing by the combination.
限制起始点火的机制是必不可少的，因为在未受干扰的细胞中复制人类基因组的 50000 个起始点是从超过 500000 个许可起始点中选择的。复制焦点时空模式的计算模型假设起始点以类似多米诺骨牌的方式随机点火，从而使稍后点火的起始点靠近最近点火的起始点。这些随机起始点火模型需要休眠起始点火信号来抑制起始点火，并抑制许可的起始点在复制叉周围约 7-120 kbp 的距离上进行被动复制。ATR 和 CHK1 激酶抑制剂增加了起始点火并增加了未受干扰细胞中的起始点密度。因此，基础 ATR 和 CHK1 激酶依赖性休眠起始点火信号抑制起始点火，并且似乎存在 ATR 激酶信号的两个阈值。少数 ATR 分子被激活用于 ATR 和 CHK1 激酶依赖性休眠起始点火信号，这对于未受干扰的细胞中的 DNA 复制是必不可少的。大多数 ATR 分子被激活用于 ATR 和 CHK1 激酶依赖性检查点信号，用于处理靶向复制叉的 DNA 损伤剂的细胞。由于 ATR 和 CHK1 激酶抑制剂增加了起始点火，并且与叉停顿和大量单链 DNA 有关，因此它们是 DNA 损伤剂。因此，ATR 和 CHK1 激酶抑制剂和 DNA 损伤剂的给药顺序可能会影响组合引起的 DNA 损伤以及组合的细胞杀伤效果。
