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Review
. 2019 May 24;10(5):398.
doi: 10.3390/genes10050398.

Preserving Genome Integrity During the Early Embryonic DNA Replication Cycles

Chames Kermi  1   2 , Antoine Aze  3 , Domenico Maiorano  4
Affiliations
Review

Preserving Genome Integrity During the Early Embryonic DNA Replication Cycles

Chames Kermi et al. Genes (Basel). .

Abstract

During the very early stages of embryonic development chromosome replication occurs under rather challenging conditions, including a very short cell cycle, absence of transcription, a relaxed DNA damage response and, in certain animal species, a highly contracted S-phase. This raises the puzzling question of how the genome can be faithfully replicated in such a peculiar metabolic context. Recent studies have provided new insights into this issue, and unveiled that embryos are prone to accumulate genetic and genomic alterations, most likely due to restricted cellular functions, in particular reduced DNA synthesis quality control. These findings may explain the low rate of successful development in mammals and the occurrence of diseases, such as abnormal developmental features and cancer. In this review, we will discuss recent findings in this field and put forward perspectives to further study this fascinating question.

Keywords: Caenorabditis elegans; DNA damage; DNA damage tolerance; Drosophila melanogaster; Xenopus laevis; iPSCs; mouse embryonic stem cells; replication stress; zebrafish.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Embryonic cell cycles. Cell cycle remodeling during the early stages of embryonic development. (a) Pre-MBT (I) and post-MBT (II) cell cycle of fast cleaving embryos (Caenorabdtis elegans, zebrafish, Drosophila and Xenopus). Onset of G1- and G2-phases appear at different developmental times depending on the organism. In zebrafish, G1 and G2 occur at MBT. In Xenopus and Drosophila G2 appears at MBT, while the G1-phase is observed upon gastrulation. (b) First (I) and second (II, Zygotic Genome Activation (ZGA) occurs at this stage in mouse) cell cycle of pre-implantation mammalian embryos. The cell cycle length of mice gastrula cells is much more contracted, notably S-phase only lasts 2 h compared to an average of 6 h in pre-implantation embryos (reviewed in [11]). Of note, length of cell cycle phases may be different between mouse and human pre-implantation embryos. Arrows indicate the direction of cell cycle progression. Letters indicated cell cycle phases.
Figure 2
Figure 2
Embryonic DNA replication fork features. Schematic representation of DNA replication forks in (a) fast cleaving embryos and (b) mouse embryonic stem cells. Question marks indicate so far unidentified proteins including Y-family translesion synthesis (TLS) pols. Rep Pols indicates replicative DNA pols. Ub indicates ubiquitin. CMG indicates the replicative helicase. Arrows indicate the direction of translocation of the fork.
Figure 3
Figure 3
Differences in the regulation of proliferation in embryos versus somatic cells. Inefficient checkpoint activation, suppression of apoptosis and a high contracted cell cycle promotes rapid and unchecked proliferation in the early embryo leading to the generation of a certain degree of genomic instability. In somatic cells, DNA damage is readily monitored by checkpoints that slow down cell proliferation to facilitate DNA repair, and as such preserve genome integrity, leading, when necessary, to permanent cell cycle arrest (senescence) or cell death (apoptosis, necrosis).
Figure 4
Figure 4
Consequences of chromosome abnormalities in early mammalian embryos. Each circle represent a blastomere, normal (blue) or having a different genetic content (orange).
Figure 5
Figure 5
Awakening of embryonic features in cancer cells? Cartoon showing the degree of appearance of embryonic features in cells during the process of malignant transformation.
See this image and copyright information in PMC

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