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.
Highlights
To maintain a stable genome, at each cell division, a cell must accurately duplicate its genetic material and distribute the newly replicated chromosomes in each daughter cell during mitosis.Dysfunctions in one of these processes are the main causes of chromosomal instability (CIN), which is defined as an increased rate of chromosomal changes
The cell undergoes a vast reorganization of the cytoskeleton and assembles the mitotic spindle apparatus; the microtubules emanating from the centrosomes connect both spindle poles to the individualized and condensed chromosomes by attaching to the kinetochore structure organized at the centromeric chromatin
The first hints about a connection between the premitotic and mitotic origins of CIN came from the identification of the role of factors known to be involved in DNA repair pathways, such as Bloom syndrome helicase (BLM) and FA proteins, during mitosis [75,76,77,78]
Summary
To maintain a stable genome, at each cell division, a cell must accurately duplicate its genetic material and distribute the newly replicated chromosomes in each daughter cell during mitosis. The study of the mechanisms underlying CFS instability has shed light on the important link between replication stress and CIN [36] They have shown that these loci often remain incompletely replicated during the S phase, leading to the persistence of replication intermediates until G2 and mitosis, when they are processed by specific pathways that, by resolving these structures, rescue cells from replication stress and allow proper sister chromatid separation and mitotic cell division [37]. The stepwise activation of ATR signaling and phosphorylation of its main downstream effector CHK1 upon different levels of replication stress or the formation of specific structures may elicit the different responses necessary to stabilize or resume replication fork function, regulate origin firing, delay cell cycle progression and repair any damage before the cell enters mitosis [45,49]. The tight coordination between the DDR pathways and cell cycle checkpoints throughout the S phase and mitosis is key to preventing genome instability [66]
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