Linking replication stress with heterochromatin formation

Abstract

The eukaryotic genome can be roughly divided into euchromatin and heterochromatin domains that are structurally and functionally distinct. Heterochromatin is characterized by its high compaction that impedes DNA transactions such as gene transcription, replication, or recombination. Beyond its role in regulating DNA accessibility, heterochromatin plays essential roles in nuclear architecture, chromosome segregation, and genome stability. The formation of heterochromatin involves special histone modifications and the recruitment and spreading of silencing complexes that impact the higher-order structures of chromatin; however, its molecular nature varies between different chromosomal regions and between species. Although heterochromatin has been extensively characterized, its formation and maintenance throughout the cell cycle are not yet fully understood. The biggest challenge for the faithful transmission of chromatin domains is the destabilization of chromatin structures followed by their reassembly on a novel DNA template during genomic replication. This destabilizing event also provides a window of opportunity for the de novo establishment of heterochromatin. In recent years, it has become clear that different types of obstacles such as tight protein-DNA complexes, highly transcribed genes, and secondary DNA structures could impede the normal progression of the replisome and thus have the potential to endanger the integrity of the genome. Multiple studies carried out in different model organisms have demonstrated the capacity of such replisome impediments to favor the formation of heterochromatin. Our review summarizes these reports and discusses the potential role of replication stress in the formation and maintenance of heterochromatin and the role that silencing proteins could play at sites where the integrity of the genome is compromised.

Genome diversity and species richness in mammals

“…These selectively neutral, or nearly neutral sequences are typically packaged into compact heterochromatin, which tends to be late replicating and devoid of actively expressed genes (Grewal and Moazed 2003, Grewal and Jia 2007, Aygün and Grewal 2010, Shermoen, McCleland et al 2010. The function of heterochromatin in the genome remains controversial, while its contribution to adaptation and evolution is an open question (Nikolov andTaddei 2016, Allshire andMadhani 2018).…”

Retrotransposons are specified as DNA replication origins in the gene-poor regions of Arabidopsis heterochromatin

“…In Arabidopsis, several TE families account for 21% of the genome and, although some of them are scattered along chromosome arms, most TEs concentrate in the pericen-tromeric heterochromatin (14,15). Whilst previous studies have reported the link between DNA replication fork progression and the establishment of heterochromatin (16), the genomic features that contribute to specify ORIs in heterochromatin have not been studied and, consequently, are very poorly understood.…”

Cross-Regulation between Transposable Elements and Host DNA Replication

“…Increased HR, if directed at the offending repetitive elements, could cause gross chromosomal rearrangements. This model would explain the role of heterochromatin in maintenance of genome integrity [103]. Loss of silencing of TE and other forms of repetitive elements leads to widespread replication-transcription conflicts that cause DNA damage localized at heterochromatic DNA, and rearrangements through non-allelic or improperly resolved HR.…”

“…Oncogenic transformation is often accompanied by increased endogenous replication stress and DNA damage [84], and the resulting genomic instability that drives cancer progression could have a TE component. Increased activity of the LINE-1 transposition machinery is a likely culprit [115,116], but considering the high TE content of the human genome, and the genome integrity phenotypes of heterochromatin mutations observed in model organisms, loss of seamless repetitive element replication might also be a significant contributor [103]. …”