H3K4 Methylation at Active Genes Mitigates Transcription-Replication Conflicts During Replication Stress

Nat Commun. 2020 Feb 10;11(1):809. doi: 10.1038/s41467-020-14595-4.

Abstract

Transcription-replication conflicts (TRCs) occur when intensive transcriptional activity compromises replication fork stability, potentially leading to gene mutations. Transcription-deposited 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Checkpoint Kinase 2 / genetics
  • Checkpoint Kinase 2 / metabolism
  • Chromatin / metabolism
  • DNA Polymerase II / metabolism
  • DNA Replication*
  • Genome, Fungal / genetics
  • Genomic Instability
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics
  • Histones / metabolism*
  • Methylation
  • Models, Genetic
  • Mutation
  • S Phase Cell Cycle Checkpoints / genetics
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription, Genetic*

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Histones
  • Saccharomyces cerevisiae Proteins
  • Histone-Lysine N-Methyltransferase
  • SET1 protein, S cerevisiae
  • Checkpoint Kinase 2
  • RAD53 protein, S cerevisiae
  • DNA Polymerase II