Abstract
Genome replication involves dealing with obstacles that can result from DNA damage but also from chromatin alterations, topological stress, tightly bound proteins or non-B DNA structures such as R loops. Experimental evidence reveals that an engaged transcription machinery at the DNA can either enhance such obstacles or be an obstacle itself. Thus, transcription can become a potentially hazardous process promoting localized replication fork hindrance and stress, which would ultimately cause genome instability, a hallmark of cancer cells. Understanding the causes behind transcription-replication conflicts as well as how the cell resolves them to sustain genome integrity is the aim of this review.
Highlights
Genome replication involves dealing with obstacles that can result from DNA damage and from chromatin alterations, topological stress, tightly bound proteins or non-B DNA structures such as R loops
Transcription elongation is coupled to mRNA packaging and splicing until it reaches the termination region, in which RNA 3′ end processing and termination factors are loaded to generate an export-competent messenger ribonucleoprotein particle and remove the RNAPII from the DNA template
A role for transcription termination factors (TTFs) in preventing T–R conflicts was first reported based on the observation that mutants in the bacterial termination factor Rho led to replication-dependent double-strand breaks (DSBs) (Washburn and Gottesman 2011)
Summary
Replication initiates bidirectionally from a well-defined and usually single origin in bacteria but from multiple and less-well-defined origins in eukaryotes. Accessibility of DNA topoisomerases ahead of the fork is restricted to certain genomic contexts, including when two forks converge (replication termination regions), heterochromatin and other topological barriers such as the nuclear envelope In these cases, further fork progression is thought to rely exclusively on fork rotation to solve the topological stress (Keszthelyi et al 2016). The negative supercoiling frequently associated with GC-rich and skewed sequences would potentially promote the formation of G4 structures and DNA–RNA hybrids (Ginno et al 2013; Manzo et al 2018) In addition to these features, accumulating evidence supports that transcription is likely the major source of replicative impairments (Fig. 1B, panel vi). DNA supercoiling and structure, genotoxic accessibility, and non-B DNA structure formation, understanding how transcription impairs fork progression requires tackling the way transcription-associated events contribute to fork stalling
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