Sexually dimorphic DNA damage responses and mutation avoidance in the mouse germline

Genes Dev. 2020 Dec 1;34(23-24):1637-1649. doi: 10.1101/gad.341602.120. Epub 2020 Nov 12.


Germ cells specified during fetal development form the foundation of the mammalian germline. These primordial germ cells (PGCs) undergo rapid proliferation, yet the germline is highly refractory to mutation accumulation compared with somatic cells. Importantly, while the presence of endogenous or exogenous DNA damage has the potential to impact PGCs, there is little known about how these cells respond to stressors. To better understand the DNA damage response (DDR) in these cells, we exposed pregnant mice to ionizing radiation (IR) at specific gestational time points and assessed the DDR in PGCs. Our results show that PGCs prior to sex determination lack a G1 cell cycle checkpoint. Additionally, the response to IR-induced DNA damage differs between female and male PGCs post-sex determination. IR of female PGCs caused uncoupling of germ cell differentiation and meiotic initiation, while male PGCs exhibited repression of piRNA metabolism and transposon derepression. We also used whole-genome single-cell DNA sequencing to reveal that genetic rescue of DNA repair-deficient germ cells (Fancm-/- ) leads to increased mutation incidence and biases. Importantly, our work uncovers novel insights into how PGCs exposed to DNA damage can become developmentally defective, leaving only those genetically fit cells to establish the adult germline.

Keywords: DNA damage; FancM; cell cycle checkpoint; fertility; genome maintenance; primordial germ cells; single-cell DNA sequencing; transposons.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle Checkpoints / genetics
  • Cell Differentiation / genetics
  • Cell Differentiation / radiation effects
  • DNA / radiation effects*
  • DNA Damage*
  • DNA Transposable Elements / radiation effects
  • Embryonic Germ Cells / cytology
  • Embryonic Germ Cells / radiation effects*
  • Female
  • Germ Cells / radiation effects*
  • Male
  • Meiosis / genetics
  • Meiosis / radiation effects
  • Mice
  • Mutation / genetics*
  • Oocytes / cytology
  • Oocytes / radiation effects
  • Pregnancy
  • RNA, Small Interfering / metabolism
  • Radiation, Ionizing*
  • Sex Factors


  • DNA Transposable Elements
  • RNA, Small Interfering
  • DNA