Working on Genomic Stability: From the S-Phase to Mitosis

Abstract

Fidelity in chromosome duplication and segregation is indispensable for maintaining genomic stability and the perpetuation of life. Challenges to genome integrity jeopardize cell survival and are at the root of different types of pathologies, such as cancer. The following three main sources of genomic instability exist: DNA damage, replicative stress, and chromosome segregation defects. In response to these challenges, eukaryotic cells have evolved control mechanisms, also known as checkpoint systems, which sense under-replicated or damaged DNA and activate specialized DNA repair machineries. Cells make use of these checkpoints throughout interphase to shield genome integrity before mitosis. Later on, when the cells enter into mitosis, the spindle assembly checkpoint (SAC) is activated and remains active until the chromosomes are properly attached to the spindle apparatus to ensure an equal segregation among daughter cells. All of these processes are tightly interconnected and under strict regulation in the context of the cell division cycle. The chromosomal instability underlying cancer pathogenesis has recently emerged as a major source for understanding the mitotic processes that helps to safeguard genome integrity. Here, we review the special interconnection between the S-phase and mitosis in the presence of under-replicated DNA regions. Furthermore, we discuss what is known about the DNA damage response activated in mitosis that preserves chromosomal integrity.

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

“…It is unclear whether this leakage underlies a low level of active forks or terminally arrested forks that do not signal to the checkpoint. Indeed, several studies have shown that replication completion at some loci in the genome, notably CFSs, can be delayed after the S phase, particularly after replication stress; thus, replication intermediates persist until G2 and mitosis [37,66]. A recent study from Lafarga and collaborators identified the RNA-binding protein TIAR as a novel component of a G2/M checkpoint that prevents cells with under-replicated or damaged DNA from entering mitosis.…”

“…ATR was shown to be recruited to centromeres in an R-loop-dependent manner, where it activates Aurora B to promote faithful microtubule binding and subsequent chromosome segregation [74]. The tight coordination between the DDR pathways and cell cycle checkpoints throughout the S phase and mitosis is thus key to preventing genome instability [66].…”

Mitotic cells can repair DNA double-strand breaks via a homology-directed pathway

“…Thus, accumulating evidence has suggested the existence of mitotic DSB repair, and this is further supported by recent results showing the existence of mitotic DNA repair synthesis [ 18 , 20 , 27 , 28 ]. Sister chromatid non-disjunction, which results in ultrafine bridges (UFBs) in anaphase, should be repaired in mitosis, and resolution of UFBs requires DNA polymerase delta subunit 3 (POLD3)-dependent unscheduled DNA synthesis, so this could provide evidence for mitotic DSB repair in somatic cells [ 20 ].…”

Kinetics of DNA Repair in Vicia faba Meristem Regeneration Following Replication Stress

“…Replication stress is a phenomenon which has serious implications for genome duplication, genome division, and genome stability [ 1 ]. Replication stress is generally described as the inhibition or slow-down of DNA replication, which leads to a highly dangerous accumulation of DNA damage in a cell.…”