DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Abstract

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.

Keywords: DNA replication stress; aneuploidy; cancer; chromosomal instability; chromosome segregation; mitosis.

Figure 1

The different types of ultrafine bridges (UFBs).

Figure 2

The impact of replication stress on the mitotic process. Diagram summarizing the type of mitotic dysfunctions occurring after replication stress. Replication stress can induce nonattached kinetochores and activate the spindle assembly checkpoint (SAC), change microtubule stability, induce multiple spindle poles due to centriole disengagement and lead to cohesion defects. SAC override might contribute to the mis-segregation of chromosomes with wrongly attached kinetochores. Changes in microtubule stability could lead to impaired error corrections that rely on the dynamic instability of microtubules. Multipolarity can occur transiently, because centrioles within one centrosome split before spindle poles cluster back together. Cohesion can be prematurely relieved at the centromere, which can induce chromosome mal-attachments because of altered kinetochore geometry. Wrongly attached kinetochores that are less efficiently corrected can favor merotelically attached chromatids, where microtubules of opposing spindle poles attach to the same kinetochore. Such chromatid appears as lagging in-between the two segregating DNA masses and can be either reintegrated into the correct daughter cell, integrated into the wrong daughter cell (thus leading to aneuploidy) or get enclosed by its own nuclear envelope (micronucleus).

Figure 3

Replication stress and mitotic defects feed chromosomal instability (CIN) in a vicious circle. Diagram summarizing the vicious circle of CIN. Replication stress induced by several endogenous and exogenous sources, represented as under-replicated DNA, leads to mitotic defects (multipolar spindles in prometaphase and metaphase or lagging chromosomes, bulky and ultrafine DNA bridges in anaphase). Mitotic defects and chromosome mis-segregation will consequently lead to s- or n-CIN (structural chromosome rearrangements, micronuclei and numerical aneuploidy). Aneuploidy-associated stressors [198] (proteotoxic, metabolic, oxidative stress and altered levels of replication factors) due to gene dosage imbalance will, in turn, fuel replication stress, thus completing the CIN propagation circle. This vicious cycle can be evaded or stopped when the accumulated genomic alterations activate elimination pathways (apoptosis, senescence or immune system-mediated killing by p53, SASP or cGAS-STING), thus breaking the cycle. ROS: Reactive oxygen species.