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DNA Breaks Due to Replication Stress Limit the Developmental Potential of Human Preimplantation Embryos

55 Pages Posted: 12 Apr 2021 Publication Status: Review Complete

See all articles by Katherine L. Palmerola

Katherine L. Palmerola

Columbia University - Division of Reproductive Endocrinology and Infertility

Selma Amrane

Columbia University - Division of Reproductive Endocrinology and Infertility

Alejandro De Los Angeles

Columbia University - Division of Molecular Genetics

Shuangyi Xu

Columbia University - Division of Molecular Genetics

Michael V. Zuccaro

Columbia University - Division of Molecular Genetics

Dashiell Massey

Cornell University - Department of Molecular Biology and Genetics

Joao De Pinho

Columbia University - Division of Reproductive Endocrinology and Infertility

Anisa Subbiah

Columbia University - Division of Reproductive Endocrinology and Infertility

Bob Prosser

Columbia University - Division of Reproductive Endocrinology and Infertility

Rogerio Lobo

Columbia University - Division of Reproductive Endocrinology and Infertility

Amnon Koren

Cornell University - Department of Molecular Biology and Genetics

Timour Baslan

Memorial Sloan Kettering Cancer Center - Cancer Biology and Genetics Program

Dieter Egli

Columbia University - Division of Reproductive Endocrinology and Infertility

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Abstract

Human cleavage stage embryos frequently acquire chromosomal aneuploidies during mitosis. We recently showed that double strand breaks (DSBs) introduced by Cas9 result in frequent chromosomal alterations. Here we show that spontaneous DSBs arise de novo during embryonic DNA replication and show as chromosomal breaks that occur primarily, in centromeric, and gene-poor areas, with the latter harboring long genes implicated in neurodevelopmental disorders, including CNTN5, IMMP2L, LRP1B, RYR2, CSMD1. While transcription-replication conflicts are not required for chromosome fragility, fragile, gene-poor regions contain long-traveling replication forks, and complete replication late in G2 phase, hours after most of the genome has been duplicated. Incomplete replication at these sites in both human and mouse zygotes, results in DSBs, whole and segmental chromosome errors, micronucleation, chromosome fragmentation and poor embryo quality. Thus, failure to complete DNA replication is a mechanism of developmental failure, and a source of detrimental genetic alterations in humans.

Keywords: human preimplantation embryo; double strand break; chromosomal mosaicism; chromosome fragility; DNA damage; late replication; replication stress; developmental abnormalities; aphidicolin; DNA polymerase; micronuclei

Suggested Citation

Palmerola, Katherine L. and Amrane, Selma and De Los Angeles, Alejandro and Xu, Shuangyi and Zuccaro, Michael V. and Massey, Dashiell and De Pinho, Joao and Subbiah, Anisa and Prosser, Bob and Lobo, Rogerio and Koren, Amnon and Baslan, Timour and Egli, Dieter, DNA Breaks Due to Replication Stress Limit the Developmental Potential of Human Preimplantation Embryos. Available at SSRN: https://ssrn.com/abstract=3825160 or http://dx.doi.org/10.2139/ssrn.3825160
This version of the paper has not been formally peer reviewed.

Katherine L. Palmerola

Columbia University - Division of Reproductive Endocrinology and Infertility ( email )

United States

Selma Amrane

Columbia University - Division of Reproductive Endocrinology and Infertility ( email )

United States

Alejandro De Los Angeles

Columbia University - Division of Molecular Genetics ( email )

3022 Broadway
New York, NY 10027
United States

Shuangyi Xu

Columbia University - Division of Molecular Genetics ( email )

3022 Broadway
New York, NY 10027
United States

Michael V. Zuccaro

Columbia University - Division of Molecular Genetics ( email )

3022 Broadway
New York, NY 10027
United States

Dashiell Massey

Cornell University - Department of Molecular Biology and Genetics

Ithaca, NY 14853
United States

Joao De Pinho

Columbia University - Division of Reproductive Endocrinology and Infertility ( email )

United States

Anisa Subbiah

Columbia University - Division of Reproductive Endocrinology and Infertility ( email )

United States

Bob Prosser

Columbia University - Division of Reproductive Endocrinology and Infertility

United States

Rogerio Lobo

Columbia University - Division of Reproductive Endocrinology and Infertility ( email )

United States

Amnon Koren

Cornell University - Department of Molecular Biology and Genetics

Ithaca, NY 14853
United States

Timour Baslan

Memorial Sloan Kettering Cancer Center - Cancer Biology and Genetics Program

New York, NY 10065
United States

Dieter Egli (Contact Author)

Columbia University - Division of Reproductive Endocrinology and Infertility ( email )

United States

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