CNRS UMR9019 Genome Integrity and Cancers, Université Paris Saclay, Gustave Roussy, 94805 Villejuif, France.
UMR144 Cell Biology and Cancer, Institut Curie, 75005 Paris, France.
Genes (Basel). 2020 Jun 10;11(6):642. doi: 10.3390/genes11060642.
Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is "replication stress", a condition in which stalled or slowly progressing replication forks interfere with timely and error-free completion of the S phase. On the other hand, mitotic errors that result in chromosome mis-segregation are the cause of numerical chromosome instability (n-CIN) and aneuploidy. In this review, we will discuss recent evidence showing that these two forms of chromosomal instability can be mechanistically interlinked. We first summarize how replication stress causes structural and numerical CIN, focusing on mechanisms such as mitotic rescue of replication stress (MRRS) and centriole disengagement, which prevent or contribute to specific types of structural chromosome aberrations and segregation errors. We describe the main outcomes of segregation errors and how micronucleation and aneuploidy can be the key stimuli promoting inflammation, senescence, or chromothripsis. At the end, we discuss how CIN can reduce cellular fitness and may behave as an anticancer barrier in noncancerous cells or precancerous lesions, whereas it fuels genomic instability in the context of cancer, and how our current knowledge may be exploited for developing cancer therapies.
染色体不稳定性 (CIN) 与许多人类疾病有关，包括神经发育或神经退行性疾病、与年龄相关的疾病和癌症，是疾病发生和进展的关键驱动因素。导致结构染色体不稳定 (s-CIN) 和结构染色体畸变的主要原因是“复制应激”，即停滞或缓慢进展的复制叉干扰 S 期的及时和无差错完成的情况。另一方面，导致染色体错误分离的有丝分裂错误是数字染色体不稳定性 (n-CIN) 和非整倍体的原因。在这篇综述中，我们将讨论最近的证据表明这两种形式的染色体不稳定性可以在机制上相互关联。我们首先总结了复制应激如何导致结构和数字 CIN，重点介绍了有丝分裂拯救复制应激 (MRRS) 和中心体脱离等机制，这些机制可以预防或导致特定类型的结构染色体畸变和分离错误。我们描述了分离错误的主要结果，以及微核形成和非整倍体如何成为促进炎症、衰老或染色体重排的关键刺激因素。最后，我们讨论了 CIN 如何降低细胞适应性，并且在非癌细胞或癌前病变中可能表现为抗癌屏障，而在癌症的背景下，它会加剧基因组不稳定性，以及我们目前的知识如何被用于开发癌症治疗方法。
