Transcription-Replication Collisions and Chromosome Fragility

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).

KU70 and CAF‐1 in Arabidopsis: Divergent roles in rDNA stability and telomere homeostasis

“…Such dysfunction could then result in DNA replication fork stalling and DNA breaks. As rDNA and telomeres are particularly sensitive genome domains and problematic templates for DNA replication (Dvorackova et al., 2015; Wu et al., 2021), a deletion‐prone NHEJ repair could be one of the mechanisms of rDNA and telomere repeat loss. However, the effect of KU70 on telomere stability in fas1 plants might interfere with its role in protection against alternative telomere lengthening, ALT (Li et al., 2011; Yu et al., 2015).…”

New insights on the evolution of nucleolar dominance in newly resynthesized hexaploid wheat Triticum zhukovskyi

“…We speculate that the silenced rDNA loci may be specifically reactivated in meiosis cells, making it tempting to conduct immunolocalization analysis of anti‐fibrillarin in interphase nuclei of paternal and maternal meiosis cells. Furthermore, the actively transcribed rDNA units from the G genome may lead to chromosome fragility through recombination due to the relatively decondensed chromatin environment and transcription–replication conflicts (Keil & Roeder, 1984; Lawrimore & Bloom, 2019; Takeuchi et al., 2003; Wu et al., 2021), while inactive rDNA units from the A m genome can be stable in the genome in the form of R‐loops and serve as a ‘first reserve’ to reduce the mutation destruction and contribute to the successful evolution of T. zhukovskyi .…”

Characteristic Hallmarks of Aging and the Impact on Carcinogenesis

“…Telomeres, the protective DNA-protein structures at the ends of eukaryotic chromosomes, are essential for genome integrity and stability [32]. Telomeres are regions composed of thousands of hexameric nucleotide repeats of the sequence TTAGGG (initially double-stranded DNA but ending with a single-stranded DNA overhang) that lie at the ends of chromosomes, usually bound by the shelterin complex to prevent telomeres from being recognized as DNA double-strand breaks (DSBs) and enabling DNA replication at the telomeric repeats, which is critical for genome stability and cell survival [76]. The extended 5′ to 3′ strand contains the G-rich telomeric repeats and is referred to as the G-strand, while the 3′ to 5′ strand is defined as the C-strand.…”