Replication stress impairs chromosome segregation and preimplantation development in human embryos.
Cell
; 185(16): 2988-3007.e20, 2022 08 04.
Article
in En
| MEDLINE
| ID: mdl-35858625
ABSTRACT
Human cleavage-stage embryos frequently acquire chromosomal aneuploidies during mitosis due to unknown mechanisms. Here, we show that S phase at the 1-cell stage shows replication fork stalling, low fork speed, and DNA synthesis extending into G2 phase. DNA damage foci consistent with collapsed replication forks, DSBs, and incomplete replication form in G2 in an ATR- and MRE11-dependent manner, followed by spontaneous chromosome breakage and segmental aneuploidies. Entry into mitosis with incomplete replication results in chromosome breakage, whole and segmental chromosome errors, micronucleation, chromosome fragmentation, and poor embryo quality. Sites of spontaneous chromosome breakage are concordant with sites of DNA synthesis in G2 phase, locating to gene-poor regions with long neural genes, which are transcriptionally silent at this stage of development. Thus, DNA replication stress in mammalian preimplantation embryos predisposes gene-poor regions to fragility, and in particular in the human embryo, to the formation of aneuploidies, impairing developmental potential.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Chromosome Breakage
/
Chromosome Segregation
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2022
Type:
Article
Affiliation country:
United States