Institute of Molecular Oncology, Section for Cellular Oncology, Georg-August University Göttingen, Göttingen Center for Molecular Biosciences (GZMB) and University Medical Center Göttingen (UMG) , Göttingen , Germany.
Cell Cycle. 2019 Oct;18(20):2770-2783. doi: 10.1080/15384101.2019.1658477. Epub 2019 Aug 25.
Chromosomal instability (CIN) causes structural and numerical chromosome aberrations and represents a hallmark of cancer. Replication stress (RS) has emerged as a driver for structural chromosome aberrations while mitotic defects can cause whole chromosome missegregation and aneuploidy. Recently, first evidence indicated that RS can also influence chromosome segregation in cancer cells exhibiting CIN, but the underlying mechanisms remain unknown. Here, we show that chromosomally unstable cancer cells suffer from very mild RS, which allows efficient proliferation and which can be mimicked by treatment with very low concentrations of aphidicolin. Both, endogenous RS and aphidicolin-induced very mild RS cause chromosome missegregation during mitosis leading to the induction of aneuploidy. Moreover, RS triggers an increase in microtubule plus end growth rates in mitosis, an abnormality previously identified to cause chromosome missegregation in cancer cells. In fact, RS-induced chromosome missegregation is mediated by increased mitotic microtubule growth rates and is suppressed after restoration of proper microtubule growth rates and upon rescue of replication stress. Hence, very mild and cancer-relevant RS triggers aneuploidy by deregulating microtubule dynamics in mitosis.
染色体不稳定性（CIN）导致结构和数量染色体异常，是癌症的一个标志。复制应激（RS）已成为结构染色体异常的驱动因素，而有丝分裂缺陷可导致整条染色体错分和非整倍体。最近，有初步证据表明，RS 也会影响表现出 CIN 的癌细胞中的染色体分离，但潜在机制尚不清楚。在这里，我们表明，染色体不稳定的癌细胞遭受非常轻微的 RS，这允许有效的增殖，并且可以通过用非常低浓度的阿霉素处理来模拟。内源性 RS 和阿霉素诱导的非常轻微的 RS 在有丝分裂过程中都会导致染色体错分，从而导致非整倍体的诱导。此外，RS 会触发有丝分裂中微管正极生长速率的增加，这是先前在癌细胞中发现的导致染色体错分的异常。事实上，RS 诱导的染色体错分是通过增加有丝分裂中的微管生长速率来介导的，并且在恢复适当的微管生长速率和挽救复制应激后被抑制。因此，非常轻微且与癌症相关的 RS 通过扰乱有丝分裂中的微管动力学引发非整倍体。
