Replication stress impairs chromosome segregation and preimplantation development in human embryos

Palmerola, Katherine L.; Amrane, Selma; Angeles, Alejandro De Los; Xu, Shuangyi; Wang, Ning; Pinho, Joao de; Zuccaro, Michael V.; Taglialatela, Angelo; Massey, Dashiell J.; Turocy, Jenna; Robles, Alex; Subbiah, Anisa; Prosser, Bob; Løbo, Rogerio A.; Ciccia, Alberto; Koren, Amnon; Baslan, Timour; Egli, Dieter

doi:10.1016/j.cell.2022.06.028

Cited by 67 publications

(77 citation statements)

References 115 publications

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“…Analysis of 53BP1 NBs (>1 μm in diameter) in G1-phase cells (cyclin A negative) showed a significant increase in NB formation in RAS-expressing cells compared with control cells ( Figures 1 G and 1H). In contrast to large 53BP1 NBs, small 53BP1 foci were reported to form at double-strand breaks (DBSs) irrespectively of replication stress ( Palmerola et al., 2022 ; Schultz et al., 2000 ). Interestingly, analysis of small 53BP1 foci (<1 μm in diameter) in G1 cells showed an increase in foci formation in RAS-expressing cells ( Figures S2 A and S2B), suggesting that RAS induced both replicative and non-replicative DNA damage.…”

Section: Resultsmentioning

confidence: 99%

“…In light of our results, TOP1-induced accelerated replication may promote mutagenesis, associated with DNA replication. Interestingly, RAS-expressing cells show an increase in single-stranded DNA (ssDNA; phosphorylated Chk1) and markers of under-replicated regions (fragile sites) ( Figures 1 I, 1J, S2 E, and S2F), raising the possibility that excess TOP1 and accelerated replication may perturb DNA replication and its proofreading and thus leave behind ssDNA lesions that may be converted to DSBs ( Palmerola et al., 2022 ). Further studies are required to shed light on the molecular mechanism(s) underlying accelerated replication-induced DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability

et al. 2022

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability

et al. 2022

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“…This is similar to findings in a non-human primate model showing that abnormal chromosomes can be encapsulated in micronuclei, which can subsequently be selectively eliminated from the embryo 34 . In human cleavage stage embryos these micronuclei have been shown to contain genetic material that originates from chromosome breakages due to replication fork stalling and DNA-damage during the first cell-cycle 35 .…”

Section: Resultsmentioning

confidence: 99%

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Regin

Lei

Deckersberg

et al. 2022

Preprint

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Aneuploidy is present in about 80% of human preimplantation embryos and is thought to largely explain our relatively low fertility. However, the percentage of aneuploid cells decreases progressively during the early cleavages and chromosomally mosaic human embryos have been shown to result in healthy newborns with normal karyotypes. These observations imply a selective loss of aneuploid cells, but the underlying mechanisms are not yet fully understood. Here, we show that, while aneuploid embryos had lower cell numbers in both trophectoderm (TE) and inner-cell-mass (ICM), the effect of aneuploidy was cell-type dependent. Aneuploid TE presented transcriptomic signatures of DNA-damage, p53-signalling and apoptosis. Immunostaining of whole embryos showed that aneuploidy results in increased proteotoxic stress, autophagy, DNA damage-mediated activated p53 and subsequent apoptosis in the TE only. In the ICM, aneuploidy impaired primitive endoderm differentiation. Our findings explain why fully aneuploid embryos fail to further develop and shed light on the mechanisms by which aneuploid cells are removed from mosaic embryos.

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“…These reports are consistent with a higher degree of chaotic aneuploidy observed in poorer quality and slower growing blastocysts (Figures 5A,B; Figures S5A,B; Figures S6A,B). Interestingly, recent work by Palmerola et al (2022) confirmed a high level of incomplete DNA replication resulting in chromosome breaks and mitotic aneuploidy in human zygotes, referred to as replication stress. It is tempting to conclude that our findings are consistent with those of Palmerola et al, (2022) with the caveat that their studies involved the use of donated vitrified MII oocytes (see also Cavazza and Schuh, 2022).…”

Section: Discussionmentioning

confidence: 99%

Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos

McCoy

Summers

McCollin

et al. 2022

Preprint

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The high incidence of aneuploidy in early human development, arising either from errors in meiosis or postzygotic mitosis, is the primary cause of pregnancy loss, miscarriage, and still birth following natural conception as well asin vitrofertilization (IVF). Preimplantation genetic testing for aneuploidy (PGT-A) has confirmed the prevalence of meiotic and mitotic aneuploidies among blastocyst-stage IVF embryos that are candidates for transfer. However, only about half of normally fertilized embryos develop to the blastocyst stagein vitro, while the others arrest at cleavage to late morula or early blastocyst stages. To achieve a more complete view of the impacts of aneuploidy, we applied a validated method of PGT-A to a large series (n = 909) of arrested embryos and trophectoderm biopsies. We then correlated observed aneuploidies with abnormalities of the first two cleavage divisions using time lapse imaging (n = 843). The combined incidence of meiotic and mitotic aneuploidies was strongly associated with blastocyst morphological grading, with the proportion ranging from 20% to 90% for the highest to lowest grades, respectively. In contrast, the incidence of aneuploidy among arrested embryos was exceptionally high (94%), dominated by mitotic aneuploidies affecting multiple chromosomes. In turn, these mitotic aneuploidies were strongly associated with abnormal cleavage divisions, such that 51% of abnormally dividing embryos possessed mitotic aneuploidies compared to only 23% of normally dividing embryos. We conclude that the combination of meiotic and mitotic aneuploidies drives arrest of human embryosin vitro, as development increasingly relies on embryonic gene expression at the blastocyst stage.

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Replication stress impairs chromosome segregation and preimplantation development in human embryos

Cited by 67 publications

References 115 publications

Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability

Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos

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