Kermi C et al. (2017), Regulation of DNA Replication in Early Embryoni...

XB-ART-53011

Genes (Basel) 2017 Jan 19;81:. doi: 10.3390/genes8010042.

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Regulation of DNA Replication in Early Embryonic Cleavages.

Kermi C , Lo Furno E , Maiorano D .

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Early embryonic cleavages are characterized by short and highly synchronous cell cycles made of alternating S- and M-phases with virtually absent gap phases. In this contracted cell cycle, the duration of DNA synthesis can be extraordinarily short. Depending on the organism, the whole genome of an embryo is replicated at a speed that is between 20 to 60 times faster than that of a somatic cell. Because transcription in the early embryo is repressed, DNA synthesis relies on a large stockpile of maternally supplied proteins stored in the egg representing most, if not all, cellular genes. In addition, in early embryonic cell cycles, both replication and DNA damage checkpoints are inefficient. In this article, we will review current knowledge on how DNA synthesis is regulated in early embryos and discuss possible consequences of replicating chromosomes with little or no quality control.

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Species referenced: Xenopus
Genes referenced: chek1 rad18 ticrr

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	Figure 1. Reactivation of cellular processes during the early development of Xenopus laevis. Apart from DNA synthesis and translation, several cellular processes are inactive during the early stages of development. These processes are restored close to the time when zygotic transcription is activated, the midblastula transition in fast cleaving embryos such as Drosophila and Xenopus.
	Figure 2. Speculative model of decreased origin density at MBT. Developmental activation of CHK1 at MBT stimulated by as yet unclear cues (question mark), induces local phosphorylation of Treslin (and probably of other targets that remain to be identified) which suppresses initiation of DNA synthesis within a replication cluster thus leading to a reduced replication origins density.
	Figure 3. Schematic representation of mechanisms leading to S-phase lengthening at the MBT in Drosophila and Xenopus. In Drosophila, the establishment of heterochromatin, concomitant to the increase in the N/C ratio, contributes to S-phase lengthening after MBT. In Xenopus, titration of maternally inherited factors by the increased N/C ratio and degradation of Cyclin E participate in increasing S-phase length at the MBT. The WEE1 gene is implicated in regulating the timer for MBT onset by acting on the stability of the Cyclin E/CDK2 complex.
	Figure 4. S- and M-phases of early embryos are insensitive to DNA damage. DNA synthesis (left); and images of Xenopus laevis embryos fertilized in vitro (right), cleaving in the absence (blue line and −UV) or presence (red line and +UV) of moderate doses of UV-C irradiation (300 J/m2). Exposure to higher UV doses results in a cell cycle block due to non-specific cross-link of proteins to chromatin and failure to decondense chromosomes.
	Figure 5. A DNA damage-tolerant replisome in early embryos? Speculative representation of replisome structure in pre- and post-MBT embryos. In pre-MBT embryos, constitutive PCNAmUb, driven by high RAD18 expression, allows recruitment of TLS Pol η to replication forks thus limiting replication fork uncoupling in front of DNA damage (UV-C lesions in this example). In this situation, formation of ssDNA, which is a prerequisite for checkpoint activation, is strongly reduced. In post-MBT embryos that contain reduced RAD18 levels, PCNAmUb requires ssDNA formation, thus leading to checkpoint activation.

References [+] :

Adachi, Study of the cell cycle-dependent assembly of the DNA pre-replication centres in Xenopus egg extracts. 1994, Pubmed, Xenbase