DNA crosslink repair safeguards genomic stability during pre-meiotic germ cell development
type: CreativeWork
description: Germ cells are single-handedly responsible for the transmission of genetic and epigenetic information (the instructions to make new life) from one generation to the next. It is therefore, of paramount importance that germ cells maintain the stability of their genome. Failure to do so can result in the transmission of de novo mutations to offspring. Germline de novo mutations are the basis of genetic disease and the foundation of genetic diversity within a species, and the substrate on which evolution acts. However, the timings and molecular origins of germline mutagenesis are not fully understood. Here we describe a fundamental role for the structure-specific endonuclease XPF-ERCC1 in Fanconi-mediated DNA crosslink repair during germ cell development in utero. Inactivation of Fanconi-mediated DNA repair results in an almost complete loss of gamete production in mice. This repair pathway is critical for the normal development of primordial germ cells (PGCs), which are the earliest germ cells to arise during embryogenesis. We find that loss of crosslink repair leads the accumulation of DNA double-strand breaks in PGCs during a narrow temporal window of development. PGCs with DNA damage phosphorylate p53 and are lost through apoptosis. The loss of PGCs in crosslink repair-deficient embryos coincides with the unique process of epigenetic reprogramming, in which PGCs erase epigenetic restraints and parental imprints during the acquisition of germline totipotency. However, we find that the remaining crosslink repair-deficient PGCs undergo the major hallmarks of epigenetic reprogramming. Furthermore, we demonstrate the both XPF-ERCC1 and Fanconi-mediated DNA crosslink repair are dispensable for meiosis in mice. Furthermore, the data presented within this Thesis sheds light on the fertility defects observed in human patients with Fanconi anaemia, and provides a plausible explanation for germ cell attrition and infertility in a complex human disease. Finally, we describe an …
abstract: Germ cells are single-handedly responsible for the transmission of genetic and epigenetic information (the instructions to make new life) from one generation to the next. It is therefore, of paramount importance that germ cells maintain the stability of their genome. Failure to do so can result in the transmission of de novo mutations to offspring. Germline de novo mutations are the basis of genetic disease and the foundation of genetic diversity within a species, and the substrate on which evolution acts. However, the timings and molecular origins of germline mutagenesis are not fully understood. Here we describe a fundamental role for the structure-specific endonuclease XPF-ERCC1 in Fanconi-mediated DNA crosslink repair during germ cell development in utero. Inactivation of Fanconi-mediated DNA repair results in an almost complete loss of gamete production in mice. This repair pathway is critical for the normal development of primordial germ cells (PGCs), which are the earliest germ cells to arise during embryogenesis. We find that loss of crosslink repair leads the accumulation of DNA double-strand breaks in PGCs during a narrow temporal window of development. PGCs with DNA damage phosphorylate p53 and are lost through apoptosis. The loss of PGCs in crosslink repair-deficient embryos coincides with the unique process of epigenetic reprogramming, in which PGCs erase epigenetic restraints and parental imprints during the acquisition of germline totipotency. However, we find that the remaining crosslink repair-deficient PGCs undergo the major hallmarks of epigenetic reprogramming. Furthermore, we demonstrate the both XPF-ERCC1 and Fanconi-mediated DNA crosslink repair are dispensable for meiosis in mice. Furthermore, the data presented within this Thesis sheds light on the fertility defects observed in human patients with Fanconi anaemia, and provides a plausible explanation for germ cell attrition and infertility in a complex human disease. Finally, we describe an …
author: Hill, Ross James
language: eng
keywords: Germ cell, DNA repair, Stem cells, DNA Crosslink repair, Fanconi anaemia
license: https://www.repository.cam.ac.uk/bitstreams/e01bf66a-1ecb-4188-a062-23231a957535/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2020-09-02
date modified: 2026-07-24T01:33:30Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.66360