Abstract
Accurate replication of the entire genome is critical for cell division and propagation. Certain regions in the genome, such as fragile sites (common fragile sites, rare fragile sites, early replicating fragile sites), rDNA and telomeres, are intrinsically difficult to replicate, especially in the presence of replication stress caused by, for example, oncogene activation during tumor development. Therefore, these regions are particularly prone to deletions and chromosome rearrangements during tumorigenesis, rendering chromosome fragility. Although, the mechanism underlying their “difficult-to-replicate” nature and genomic instability is still not fully understood, accumulating evidence suggests transcription might be a major source of endogenous replication stress (RS) leading to chromosome fragility. Here, we provide an updated overview of how transcription affects chromosome fragility. Furthermore, we will use the well characterized common fragile sites (CFSs) as a model to discuss pathways involved in offsetting transcription-induced RS at these loci with a focus on the recently discovered atypical DNA synthesis repair pathway Mitotic DNA Synthesis (MiDAS).
Highlights
To proliferate, a cell needs to go through a division cycle, where it duplicates its chromosomes in S phase
It is thought that a co-directional encounter is less toxic to cells than the head-on collision. Consistent with this notion, an in vitro study suggested that a reconstituted Escherichia coli replisome can remove or bypass a co-directional RNA polymerase (RNAP) and use the newly synthesized mRNA as a primer to carry on DNA synthesis (Liu et al, 1993; Pomerantz and O’Donnell, 2008)
Many oncogenes act as growth factors to support proliferation by upregulating transcription factors which in turn can stimulate RNA synthesis (Kotsantis et al, 2016)
Summary
A cell needs to go through a division cycle, where it duplicates its chromosomes in S phase. It is thought that a co-directional encounter is less toxic to cells than the head-on collision Consistent with this notion, an in vitro study suggested that a reconstituted Escherichia coli replisome can remove or bypass a co-directional RNAP and use the newly synthesized mRNA as a primer to carry on DNA synthesis (Liu et al, 1993; Pomerantz and O’Donnell, 2008). It is much more stable than double stranded DNA, and can directly interfere with DNA replication leading to fork stalling or collapse (Aguilera and García-Muse, 2012; SantosPereira and Aguilera, 2015) Consistent with this idea, R-loops are significantly enriched at head-on regions in human cells, and introducing a head-on collision on a plasmid causes plasmid loss in a R-loop dependent manner (Hamperl et al, 2017)
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