The helicase RTEL1 is conserved in eukaryotes and resolves DNA secondary structures that otherwise would delay replication. As it predominantly resolves G-quadruplexes of G-rich sequences that occur in telomeres, it is required for proper telomere replication. RTEL1 may also be required for replication outside of telomeres, and absence of RTEL1 causes replication stress. However, the link between replication stress and epigenetic silencing is less clear. In heterochromatin, silencing is predominantly due to DNA methylation; however, recently, examples of DNA-methylation-independent pathways for epigenetic silencing have been uncovered. In a screen for DNA-methylation-independent reactivation of a normally silenced reporter transgene, rtel1 mutants were uncovered.
The researchers found that in these rtel1 mutants, gene expression is globally increased. Most of the upregulated genes are protein-coding genes that are normally repressed by the H3K27me3 histone mark. In the rtel1 mutants, higher-order chromatin organization is not affected, but the H3K27me3 level at de-repressed genes is slightly reduced. In addition to protein-coding genes, a low number of TEs located in heterochromatic regions are also upregulated in rtel1 mutants. However, this was not due to decreased DNA methylation, as these sites were hypermethylated and, additionally, had a higher level of H3K27me3. Interestingly, induction of DNA crosslinks phenocopy the rtel1 mutants, suggesting that replication stress is causing the de-repression. This is also supported by enhanced de-repression when FANCJB, a related helicase involved in repair of DNA crosslinks, is also mutated. These data suggest a model according to which replication stress leads not only to epigenetic perturbations but also to a time window in which the transcription machinery can access genes within the replication fork that are normally silenced.
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