H3K4 methylation at active genes mitigates transcription-replication conflicts during replication stress
H3K4 methylation at active genes mitigates transcription-replication conflicts during replication stress
复制标题
DOI：
10.1038/s41467-020-14595-4
复制
发表时间：
2020-02-10
影响因子：
16.6
通讯作者：
Kao, Cheng-Fu
中科院分区：
文献类型：
--
作者：
Chong, Shin Yen;Cutler, Sam;Kao, Cheng-Fu
当密集的转录活动损害复制叉稳定性时，就会发生转录-复制冲突 (TRC)，从而可能导致基因突变。转录沉积的 H3K4 甲基化 (H3K4me) 与对 TRC 敏感的区域相关；然而，H3K4me 和 TRC 之间的相互作用尚不清楚。在这里，我们发现 H3K4me 会加剧检查点缺陷细胞中 TRC 诱导的复制失败，而甲基化 H3K4 的存在会减慢正在进行的复制。 S 期检查点活性和 H3K4me 对于复制应激下忠实的 DNA 合成至关重要，特别是在 H3K4me 存在最多且 TRC 最常出现的高度转录区域。 H3K4me 通过减慢正在进行的复制来减轻 TRC，类似于减速带如何减慢汽车的速度。这些发现确立了这样的概念：H3K4me 定义了基因组区域的转录状态，并保护基因组免受 TRC 介导的复制应激和不稳定性的影响。
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.