LSD1 is required for euchromatic origin firing and replication timing.

Abstract

The chromatin-based rule governing the selection and activation of replication origins remains to be elucidated. It is believed that DNA replication initiates from open chromatin domains; thus, replication origins reside in open and active chromatin. However, we report here that lysine-specific demethylase 1 (LSD1), which biochemically catalyzes H3K4me1/2 demethylation favoring chromatin condensation, interacts with the DNA replication machinery in human cells. We find that LSD1 level peaks in early S phase, when it is required for DNA replication by facilitating origin firing in euchromatic regions. Indeed, euchromatic zones enriched in H3K4me2 are the preferred sites for the pre-replicative complex (pre-RC) binding. Remarkably, LSD1 deficiency leads to a genome-wide switch of replication from early to late. We show that LSD1-engaged DNA replication is mechanistically linked to the loading of TopBP1-Interacting Checkpoint and Replication Regulator (TICRR) onto the pre-RC and subsequent recruitment of CDC45 during origin firing. Together, these results reveal an unexpected role for LSD1 in euchromatic origin firing and replication timing, highlighting the importance of epigenetic regulation in the activation of replication origins. As selective inhibitors of LSD1 are being exploited as potential cancer therapeutics, our study supports the importance of leveraging an appropriate level of LSD1 to curb the side effects of anti-LSD1 therapy.

• Authors: Yue Wang, Yunchao Huang, Edith Cheng, Xinhua Liu, Yu Zhang, Jianguo Yang, Jordan T F Young, Grant W Brown, Xiaohan Yang, Yongfeng Shang
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 7 Issue 1 Pg. 102 (04 13 2022) ISSN: 2059-3635 [Electronic] England
• PMID: 35414135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Cell Cycle Proteins
• Chromatin
• TICRR protein, human
• Histone Demethylases
• KDM1A protein, human

Topics

• Cell Cycle Proteins (genetics)
• Cell Nucleus
• Chromatin (genetics)
• Epigenesis, Genetic
• Histone Demethylases (genetics)
• Humans
• Replication Origin (genetics)