H3K4 methylation at active genes mitigates transcription-replication conflicts during replication stress

Abstract

Transcription-replication conflicts (TRCs) occur when intensive transcriptional activity compromises replication fork stability, potentially leading to gene mutations. Transcriptiondeposited H3K4 methylation (H3K4me) is associated with regions that are susceptible to TRCs; however, the interplay between H3K4me and TRCs is unknown. Here we show that H3K4me aggravates TRC-induced replication failure in checkpoint-defective cells, and the presence of methylated H3K4 slows down ongoing replication. Both S-phase checkpoint activity and H3K4me are crucial for faithful DNA synthesis under replication stress, especially in highly transcribed regions where the presence of H3K4me is highest and TRCs most often occur. H3K4me mitigates TRCs by decelerating ongoing replication, analogous to how speed bumps slow down cars. These findings establish the concept that H3K4me defines the transcriptional status of a genomic region and defends the genome from TRC-mediated replication stress and instability.

Mutation bias shapes gene evolution inArabidopsis thaliana

“…This provides an opportunity for mutation rates to evolve in beneficial directions (e.g., lower mutation rates in cytogenetic states characteristic of essential housekeeping genes where mutations are more likely to be deleterious). Indeed, processes facilitating reduced mutation rates in genic regions 22,29,33 and active genes 15,17,21,24,34 have already been documented in recent years. These discoveries are consistent with contemporary theoretical predictions from population genetics that beneficial mutation rates could readily evolve even in the face of genetic drift if mutation rates are linked to gene regulation or common sequence and epigenomic features 3,8 .…”

“…The observed negative correlation between GC content and mutation rate was consistent with other observations of lower mutation rate in GC rich regions 23,[39][40][41][42] and mechanistically with both GC biased gene conversion 43 and lower rates of cytosine deamination in GC rich regions 10,[44][45][46][47] . Furthermore, the histone modifications H3K4me1 and H3K27ac are known to be associated with lower mutation rates, particularly in active genes 21,[48][49][50] , and several studies have revealed explicit connections between H3K36me3 and DNA mismatch repair 13,16,17 . These chromatin marks were enriched in gene bodies (Fig.…”

“…And while reports of non-random relationships between mutation rates and fitness consequences have been previously made, these have been questioned because they have largely relied on substitution rates in natural populations rather than direct measures of de novo mutations 3,9-12 .More recently though, discoveries in genome biology have inspired a reevaluation of classical theories of mutation rate evolution. It is now recognized that mutation rates across genomes are influenced by DNA sequence composition, epigenomic features, and bias in the targets of DNA repair mechanisms 5,6,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . It is also known that broad classes of genes (e.g., housekeeping genes) exist in distinct cytogenetic (DNA sequence + epigenomic) states.…”

Set1-dependent H3K4 methylation becomes critical for DNA replication fork progression in response to changes in S phase dynamics inSaccharomyces cerevisiae

“…The slower recovery of set1Δ from HU exposure is not the consequence of a defect in origin initiation but most likely in the processing of HU-stalled forks. Second, Set1 has a role in protecting the genome from TRCs occurrence with the transcription-deposited H3K4 methylation decelerating the fork progression at highly transcribed regions [32].…”

“…Accordingly, the DNA damage checkpoint acts together with the spindle assembly checkpoint to restrict the growth of orc5-1 set1Δ cells. Because orc5-1 set1Δ viability is decreased by the lack of RNase H activity but rescued by the reduction of histone gene dosage, we propose that the role Set1 plays in TRCs limitation [32] becomes critical when replication fork velocity is increased due to the orc5-1 mutation. On another hand, orc5-1 set1Δ cell death is partly the consequence of reactive oxygen species (ROS) accumulation, likely in response to DNA damage.…”