Protection of the C. elegans germ cell genome depends on diverse DNA repair pathways during normal proliferation

Abstract

Maintaining genome integrity is particularly important in germ cells to ensure faithful transmission of genetic information across generations. Here we systematically describe germ cell mutagenesis in wild-type and 61 DNA repair mutants cultivated over multiple generations. ~44% of the DNA repair mutants analysed showed a >2-fold increased mutagenesis with a broad spectrum of mutational outcomes. Nucleotide excision repair deficiency led to higher base substitution rates, whereaspolh-1(Polη) andrev-3(Polζ) translesion synthesis polymerase mutants resulted in 50–400 bp deletions. Signatures associated with defective homologous recombination fall into two classes: 1)brc-1/BRCA1andrad-51/RAD51 paralog mutants showed increased mutations across all mutation classes, 2)mus-81/MUS81andslx-1/SLX1nuclease, andhim-6/BLM,helq-1/HELQorrtel-1/RTEL1helicase mutants primarily accumulated structural variants. Repetitive and G-quadruplex sequence-containing loci were more frequently mutated in specific DNA repair backgrounds. Tandem duplications embedded in inverted repeats were observed inhelq-1helicase mutants, and a unique pattern of ‘translocations’ involving homeologous sequences occurred inrip-1recombination mutants.atm-1/ATM checkpoint mutants harboured structural variants specifically enriched in subtelomeric regions. Interestingly, locally clustered mutagenesis was only observed for combinedbrc-1andcep-1/p53 deficiency. Our study provides a global view of how different DNA repair pathways contribute to prevent germ cell mutagenesis.