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

Shin Yen Chong, Sam Cutler, Jing-Jer Lin, Cheng-Hung Tsai, Huai-Kuang Tsai, Sue Biggins, Toshio Tsukiyama, Yi-Chen Lo () and Cheng-Fu Kao ()
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Shin Yen Chong: Academia Sinica, Nankang
Sam Cutler: Fred Hutchinson Cancer Research Center
Jing-Jer Lin: National Taiwan University College of Medicine
Cheng-Hung Tsai: Academia Sinica, Nankang
Huai-Kuang Tsai: Academia Sinica, Nankang
Sue Biggins: Fred Hutchinson Cancer Research Center
Toshio Tsukiyama: Fred Hutchinson Cancer Research Center
Yi-Chen Lo: National Taiwan University
Cheng-Fu Kao: Academia Sinica, Nankang

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14595-4

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