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

• Published in: PloS one Vol. 16; no. 4; p. e0250291
• Main Authors: Meier, Bettina, Volkova, Nadezda V, Hong, Ye, Bertolini, Simone, González-Huici, Víctor, Petrova, Tsvetana, Boulton, Simon, Campbell, Peter J, Gerstung, Moritz, Gartner, Anton
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.04.2021; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Biology and life sciences; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell Proliferation; Chromosome Mapping; Deoxyribonucleases - genetics; Deoxyribonucleases - metabolism; 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; Endonucleases - genetics; Endonucleases - metabolism; Evaluation; Gene Expression Regulation; Genetic aspects; Genome, Helminth; Germ cells; Germ Cells - cytology; Germ Cells - metabolism; Isoenzymes - genetics; Isoenzymes - metabolism; Mutation; Rad51 Recombinase - genetics; Rad51 Recombinase - metabolism; Research and Analysis Methods; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0250291

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.