Fundación Instituto Leloir - Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo de Investigaciones Científicas y Técnicas, Avenida Patricias Argentinas 435, C1405BWE Buenos Aires, Argentina.
Fundación Instituto Leloir - Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo de Investigaciones Científicas y Técnicas, Avenida Patricias Argentinas 435, C1405BWE Buenos Aires, Argentina.
J Mol Biol. 2021 May 14;433(10):166949. doi: 10.1016/j.jmb.2021.166949. Epub 2021 Mar 18.
Checkpoint Kinase 1 (Chk1) prevents DNA damage by adjusting the replication choreography in the face of replication stress. Chk1 depletion provokes slow and asymmetrical fork movement, yet the signals governing such changes remain unclear. We sought to investigate whether poly(ADP-ribose) polymerases (PARPs), key players of the DNA damage response, intervene in the DNA replication of Chk1-depleted cells. We demonstrate that PARP inhibition selectively alleviates the reduced fork elongation rates, without relieving fork asymmetry in Chk1-depleted cells. While the contribution of PARPs to fork elongation is not unprecedented, we found that their role in Chk1-depleted cells extends beyond fork movement. PARP-dependent fork deceleration induced mild dormant origin firing upon Chk1 depletion, augmenting the global rates of DNA synthesis. Thus, we have identified PARPs as novel regulators of replication fork dynamics in Chk1-depleted cells.
检查点激酶 1（Chk1）通过在面对复制应激时调整复制协调来防止 DNA 损伤。Chk1 耗竭会引起缓慢且不对称的叉移动，但控制这些变化的信号仍不清楚。我们试图研究聚（ADP-核糖）聚合酶（PARPs），即 DNA 损伤反应的关键参与者，是否干预 Chk1 耗竭细胞的 DNA 复制。我们证明，PARP 抑制选择性地缓解了叉延伸速率的降低，而没有缓解 Chk1 耗竭细胞中的叉不对称性。虽然 PARPs 对叉延伸的贡献并非前所未有，但我们发现它们在 Chk1 耗竭细胞中的作用超出了叉运动。PARP 依赖性叉减速在 Chk1 耗竭时诱导轻微的休眠起始点火，增加了 DNA 合成的全局速率。因此，我们已经确定 PARPs 是 Chk1 耗竭细胞中复制叉动力学的新型调节剂。
