Embryonic genome instability upon DNA replication timing program emergence

Saori Takahashi, Hirohisa Kyogoku (), Takuya Hayakawa, Hisashi Miura, Asami Oji, Yoshiko Kondo, Shin-ichiro Takebayashi, Tomoya S. Kitajima () and Ichiro Hiratani ()
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Saori Takahashi: RIKEN Center for Biosystems Dynamics Research (BDR)
Hirohisa Kyogoku: RIKEN Center for Biosystems Dynamics Research (BDR)
Takuya Hayakawa: Mie University
Hisashi Miura: RIKEN Center for Biosystems Dynamics Research (BDR)
Asami Oji: RIKEN Center for Biosystems Dynamics Research (BDR)
Yoshiko Kondo: RIKEN Center for Biosystems Dynamics Research (BDR)
Shin-ichiro Takebayashi: Mie University
Tomoya S. Kitajima: RIKEN Center for Biosystems Dynamics Research (BDR)
Ichiro Hiratani: RIKEN Center for Biosystems Dynamics Research (BDR)

Nature, 2024, vol. 633, issue 8030, 686-694

Abstract: Abstract Faithful DNA replication is essential for genome integrity1–4. Under-replicated DNA leads to defects in chromosome segregation, which are common during embryogenesis5–8. However, the regulation of DNA replication remains poorly understood in early mammalian embryos. Here we constructed a single-cell genome-wide DNA replication atlas of pre-implantation mouse embryos and identified an abrupt replication program switch accompanied by a transient period of genomic instability. In 1- and 2-cell embryos, we observed the complete absence of a replication timing program, and the entire genome replicated gradually and uniformly using extremely slow-moving replication forks. In 4-cell embryos, a somatic-cell-like replication timing program commenced abruptly. However, the fork speed was still slow, S phase was extended, and markers of replication stress, DNA damage and repair increased. This was followed by an increase in break-type chromosome segregation errors specifically during the 4-to-8-cell division with breakpoints enriched in late-replicating regions. These errors were rescued by nucleoside supplementation, which accelerated fork speed and reduced the replication stress. By the 8-cell stage, forks gained speed, S phase was no longer extended and chromosome aberrations decreased. Thus, a transient period of genomic instability exists during normal mouse development, preceded by an S phase lacking coordination between replisome-level regulation and megabase-scale replication timing regulation, implicating a link between their coordination and genome stability.

Date: 2024
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DOI: 10.1038/s41586-024-07841-y

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