Polq-Mediated End Joining Is Essential for Surviving DNA Double-Strand Breaks during Early Zebrafish Development

• Zebrafish without the alt-EJ polymerase Polq develop into viable and fertile adults
• DNA double-strand breaks are lethal to polq mutant zebrafish
• Cas9-induced mutation profiles differ between the wild-type and polq mutants
• The alt-EJ pathway repairs double-strand breaks in zebrafish embryos

SummaryError-prone repair of DNA double-strand breaks (DSBs) has been postulated to occur through classical non-homologous end joining (NHEJ) in systems ranging from nematode somatic tissues to zebrafish embryos. Contrary to this model, we show that zebrafish embryos mutant for DNA polymerase theta (Polq), a critical component of alternative end joining (alt-EJ), cannot repair DSBs induced by CRISPR/Cas9 or ionizing radiation. In the absence of DSBs, polq mutants are phenotypically normal, but they do not survive mutagenesis and display dramatic differences in the mutation profiles compared with the wild-type. These results show that alt-EJ repair is essential and dominant during the early development of a vertebrate.

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