Translesion synthesis polymerases are dispensable for C. elegans reproduction but suppress genome scarring by polymerase theta-mediated end joining

Bostelen, Ivo van; Schendel, Robin van; Romeijn, Ron J.; Tijsterman, Marcel

doi:10.1371/journal.pgen.1008759

Cited by 16 publications

(16 citation statements)

References 60 publications

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“…Our data suggest that REV-3 and likely POLH-1 prevent DNA breaks by reading across damaged bases that seemingly also occur in the absence of exogenous DNA damage which triggers TLS activity and produces a similar signature. Our results on REV-3 and POLH-1 are in line with earlier findings in C. elegans (Schimmel et al 2019;Roerink et al 2014;van Schendel et al 2016;van Bostelen et al 2020) and studies in yeast and mammalian cells (Lawrence and Hinkle 1996;Lange et al 2012).…”

Section: Translesion Synthesis (Tls)supporting

confidence: 92%

Systematic analysis of mutational spectra associated with DNA repair deficiency inC. elegans

Meier

Volkova

Hong

et al. 2020

Preprint

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Genome integrity is particularly important in germ cells to faithfully preserve genetic information across generations. As yet little is known about the contribution of various DNA repair pathways to prevent mutagenesis. Using the C. elegans model we analyse mutational spectra that arise in wild-type and 61 DNA repair and DNA damage response mutants cultivated over multiple generations. Overall, 44% of lines show >2-fold increased mutagenesis with a broad spectrum of mutational outcomes including changes in single or multiple types of base substitutions induced by defects in base excision or nucleotide excision repair, or elevated levels of 50-400 bp deletions in translesion polymerase mutants rev-3(pol ζ) and polh-1(pol η). Mutational signatures associated with defective homologous recombination fall into two classes: 1) mutants lacking brc-1/BRCA1 or rad-51/RAD51 paralogs show elevated base substitutions, indels and structural variants, while 2) deficiency for MUS-81/MUS81 and SLX-1/SLX1 nucleases, and HIM-6/BLM, HELQ-1/HELQ and RTEL-1/RTEL1 helicases primarily cause structural variants. Genome-wide investigation of mutagenesis patterns identified elevated rates of tandem duplications often associated with inverted repeats in helq-1 mutants, and a unique pattern of 'translocation' events involving homeologous sequences in rip-1 paralog mutants. atm-1/ATM DNA damage checkpoint mutants harboured complex structural variants enriched in subtelomeric regions, and chromosome end-to-end fusions. Finally, while inactivation of the p53-like gene cep-1 did not affect mutagenesis, combined brc-1 cep-1 deficiency displayed increased, locally clustered mutagenesis. In summary, we provide a global view of how DNA repair pathways prevent germ cell mutagenesis. Endogenous mutagenesis can be caused by nucleotide mis-incorporation during replication and by reactive cellular metabolites. Hydrolytic reactions trigger abundant depurination and depyrimidination events, and the deamination of cytosine and 5-methylcytosine (for review (Lindahl and Barnes 2000)). Reactive oxygen species, byproducts of oxidative phosphorylation and oxygen-dependent enzymatic processes, induce 10,000-100,000 DNA lesions per cell per day including base modifications such as 8-oxo-dG, thymine glycol and DNA single-strand breaks (Ames et al. 1993). In addition, enzymatic and non-enzymatic mechanisms lead to base methylations. For instance, 3-methyladenine and 3-methyl-cytosine can lead to mutations by blocking replication and O 6 -methyl-guanine leads to G>A changes (for review (Lindahl and Barnes 2000)). Metabolic byproducts such as reactive aldehydes form DNA adducts that can crosslink bases on two complementary DNA strands generating obstacles to replication and transcription. DNA double-strand breaks (DSBs) are one of the most toxic DNA lesions and arise when the replication fork is stalled by base modifications, repetitive DNA, DNA sequences prone to form tertiary structures, or collision with the transcription machinery (Mehta and Haber 2014). Neverth...

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Section: Translesion Synthesis (Tls)supporting

confidence: 92%

Systematic analysis of mutational spectra associated with DNA repair deficiency inC. elegans

Meier

Volkova

Hong

et al. 2020

Preprint

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“…The DSB is then repaired by an error-prone mechanism based on DNA polymerase theta (POLQ) leading to specific DNA deletions ( 113 ). Interestingly, translesion synthesis DNA polymerases were found to protect C. elegans from genomic deletions caused by G4-induced replication blocks ( 114 ). As molecular and genetic differences exist between Caenorhabditis elegans and mammalian cells, these mechanisms remain to be defined in human cells.…”

Section: Introductionmentioning

confidence: 99%

G-quadruplex–R-loop interactions and the mechanism of anticancer G-quadruplex binders

Miglietta

Russo

Capranico

2020

Nucleic Acids Research

101

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Genomic DNA and cellular RNAs can form a variety of non-B secondary structures, including G-quadruplex (G4) and R-loops. G4s are constituted by stacked guanine tetrads held together by Hoogsteen hydrogen bonds and can form at key regulatory sites of eukaryote genomes and transcripts, including gene promoters, untranslated exon regions and telomeres. R-loops are 3-stranded structures wherein the two strands of a DNA duplex are melted and one of them is annealed to an RNA. Specific G4 binders are intensively investigated to discover new effective anticancer drugs based on a common rationale, i.e.: the selective inhibition of oncogene expression or specific impairment of telomere maintenance. However, despite the high number of known G4 binders, such a selective molecular activity has not been fully established and several published data point to a different mode of action. We will review published data that address the close structural interplay between G4s and R-loops in vitro and in vivo, and how these interactions can have functional consequences in relation to G4 binder activity. We propose that R-loops can play a previously-underestimated role in G4 binder action, in relation to DNA damage induction, telomere maintenance, genome and epigenome instability and alterations of gene expression programs.

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“…Our results on REV-3 and POLH-1 are in line with previous findings in C . elegans [ 18 , 53 – 55 ], yeast, and mammalian cells [ 56 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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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.

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Translesion synthesis polymerases are dispensable for C. elegans reproduction but suppress genome scarring by polymerase theta-mediated end joining

Cited by 16 publications

References 60 publications

Systematic analysis of mutational spectra associated with DNA repair deficiency inC. elegans

Systematic analysis of mutational spectra associated with DNA repair deficiency inC. elegans

G-quadruplex–R-loop interactions and the mechanism of anticancer G-quadruplex binders

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

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