# Causes and Consequences of DNA Replication Stress in the Mammalian Preimplantation Embryo

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $737,732

## Abstract

Project Summary/Abstract
The genome of the early embryo provides the genetic information of the adult and thereby determines the
health of a person. Surprisingly, though an intact genome is paramount to normal development, the genome of
some mammalian species is highly unstable, including in human. Cleavage-stage embryos acquire high levels
of DNA damage and frequent chromosomal abnormalities that adversely affect developmental potential. We
recently showed that the key reason for these abnormalities are high levels of DNA replication stress during
the first cell cycles. The causes of replication stress are not known, and we are only beginning to understand
the consequences. Therefore, there is a strong rationale to study DNA replication in the mammalian embryo.
A hypothesis central to this proposal is that DNA replication stress is caused by epigenetic remodeling during
the first cell cycles. We furthermore hypothesize that the dynamics of DNA replication, also called DNA
replication timing, predispose specific genomic regions to instability and chromosome breakage. We will test
this hypothesis in three specific Aims. In Aim1, we will identify the causes of DNA replication stress. In Aim2,
we will characterize replication timing during preimplantation development, identify its molecular determinants
in the preimplantation embryo, and correlate these with the sites of chromosome breakage determined in
Aim3. The proposed work is innovative, because it focuses on an essential process - the replication of the DNA
- that has thus far not been examined as a developmentally relevant factor in mammals, and which has not yet
been investigated as a source of genetic change. It is also innovative because of the use of animal model
systems which accurately reproduce the defects seen in human cells.
The contribution is significant, because the proposed studies will lead to an understanding of the causes,
mechanisms, and consequences of genome instability in the first few cell divisions of mammalian
development. The work proposed will help understand the source of both normal as well as disease-causing
genetic variation in the genome.

## Key facts

- **NIH application ID:** 10779608
- **Project number:** 1R01HD113698-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Dieter Meinrad Egli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $737,732
- **Award type:** 1
- **Project period:** 2024-07-23 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10779608

## Citation

> US National Institutes of Health, RePORTER application 10779608, Causes and Consequences of DNA Replication Stress in the Mammalian Preimplantation Embryo (1R01HD113698-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10779608. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*