Abstract
Replication of the eukaryotic genome is a highly regulated process and stringent control is required to maintain genome integrity. In this review, we will discuss the many aspects of the chromatin and nuclear environment that play key roles in the regulation of both unperturbed and stressed replication. Firstly, the higher order organisation of the genome into A and B compartments, topologically associated domains (TADs) and sub-nuclear compartments has major implications in the control of replication timing. In addition, the local chromatin environment defined by non-canonical histone variants, histone post-translational modifications (PTMs) and enrichment of factors such as heterochromatin protein 1 (HP1) plays multiple roles in normal S phase progression and during the repair of replicative damage. Lastly, we will cover how the spatial organisation of stalled replication forks facilitates the resolution of replication stress.
Highlights
Faithful replication of the genome is important to allow successful inheritance of genetic material from parental to daughter cells in all organisms
Origin firing does not happen simultaneously across the genome; instead, different regions are replicated at different stages throughout S phase and this process is coordinated by various factors such as the local chromatin environment and sub-nuclear localisation
heterochromatin protein 1 (HP1) retention on heterochromatin has been implicated in preventing homology-directed repair of heterochromatic DSBs and mobilisation of HP1β plays a role in the activation of DNA damage response (DDR) signalling (Ayoub et al, 2008; Kalousi et al, 2015)
Summary
Faithful replication of the genome is important to allow successful inheritance of genetic material from parental to daughter cells in all organisms. Origin firing does not happen simultaneously across the genome; instead, different regions are replicated at different stages throughout S phase and this process is coordinated by various factors such as the local chromatin environment and sub-nuclear localisation. The local chromatin environment defined by composition of these nucleosomes, histone post-translational modifications (PTMs) and enrichment of non-histone proteins can affect the levels of transcription and chromatin compaction In this sense, chromatin is categorised into relaxed, transcriptionally active euchromatin and compact, transcriptionally inactive heterochromatin. Genome organisation has major regulatory roles in the repair of DNA damage and in faithful DNA replication In this Review, we will outline how the organisation of the genome, ranging from higher order spatial arrangement to the local chromatin environment, impacts the complex process of replication and the response to replication stress
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