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

PLoS One. 2021 Apr 27;16(4):e0250291. doi: 10.1371/journal.pone.0250291. eCollection 2021.

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, whereas polh-1(Polη) and rev-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/BRCA1 and rad-51/RAD51 paralog mutants showed increased mutations across all mutation classes, 2) mus-81/MUS81 and slx-1/SLX1 nuclease, and him-6/BLM, helq-1/HELQ or rtel-1/RTEL1 helicase 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 in helq-1 helicase mutants, and a unique pattern of 'translocations' involving homeologous sequences occurred in rip-1 recombination mutants. atm-1/ATM checkpoint mutants harboured structural variants specifically enriched in subtelomeric regions. Interestingly, locally clustered mutagenesis was only observed for combined brc-1 and cep-1/p53 deficiency. Our study provides a global view of how different DNA repair pathways contribute to prevent germ cell mutagenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Proliferation
  • Chromosome Mapping
  • DNA Damage
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Repair*
  • DNA Replication
  • DNA, Helminth / genetics*
  • DNA, Helminth / metabolism
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism
  • Deoxyribonucleases / genetics
  • Deoxyribonucleases / metabolism
  • Endonucleases / genetics
  • Endonucleases / metabolism
  • Gene Expression Regulation*
  • Genome, Helminth*
  • Germ Cells / cytology
  • Germ Cells / metabolism*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mutation*
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism

Substances

  • BRC-1 protein, C elegans
  • Caenorhabditis elegans Proteins
  • DNA, Helminth
  • HIM-6 protein, C elegans
  • Isoenzymes
  • Rad51 Recombinase
  • rad-51 protein, C elegans
  • DNA-Directed DNA Polymerase
  • POLH-1 protein, C elegans
  • Deoxyribonucleases
  • Endonucleases
  • MUS-81 protein, C elegans
  • SLX-1 protein, C elegans
  • HELQ-1 protein, C elegans
  • rcq-5 protein, C elegans
  • DNA Helicases