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Dynamic interplay of cNHEJ and MMEJ pathways of DNA double-strand break repair during embryonic development in

Mathieu Carrara1,2, Anne-Laure Gaillard1, Alice Brion2

  • 1Physiologie Moléculaire et Adaptation (PhyMA, UMR7221), Muséum national d'Histoire naturelle, CNRS, Paris, France.

Scientific Reports
|February 10, 2025
PubMed

Insights

Canonical non homologous end-joining (cNHEJ) and microhomology-mediated end-joining (MMEJ) play dynamic roles in zebrafish development. Their importance varies with developmental stage and response to DNA damage.

Area of Science:

  • Genetics
  • Developmental Biology
  • Molecular Biology

Background:

  • Double-strand breaks (DSBs) are critical DNA lesions.
  • Repair mechanisms like cNHEJ and MMEJ can lead to mutations.
  • Understanding these pathways' roles in development is crucial.

Purpose of the Study:

  • To investigate the differential roles of cNHEJ and MMEJ in zebrafish embryonic development.
  • To analyze gene expression patterns of cNHEJ and MMEJ factors.
  • To assess the impact of pathway inactivation on development and DNA repair.

Main Methods:

  • Gene expression analysis of cNHEJ and MMEJ factors during zebrafish development.
  • Inactivation of key MMEJ factors (nLig3, Polθ) and cNHEJ factor (DNA ligase 4).
  • Assessment of zebrafish embryonic and larval development, ionizing radiation sensitivity, and Cas9-mediated DSB repair.

Main Results:

  • MMEJ factor inactivation (nLig3, Polθ) did not impair development but sensitized embryos to radiation; Polθ deficiency altered mutation spectra.
  • cNHEJ factor inactivation (DNA ligase 4) caused larval growth defects but did not affect radiation sensitivity or Cas9-mediated DSB repair.
  • Expression of cNHEJ and MMEJ genes was dynamic and tissue-specific during development.

Conclusions:

  • cNHEJ and MMEJ pathways exhibit dynamic and context-dependent functions in zebrafish development.
  • These pathways have differential requirements during development and in response to genotoxic stress.
  • The study highlights distinct roles for nLig3, Polθ, and DNA ligase 4 in maintaining genomic integrity and development.
Keywords:
DNA repairMMEJZebrafishcNHEJ

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