Combined loss of three DNA damage response pathways renders C. elegans intolerant to light

Bostelen, Ivo van; Tijsterman, Marcel

doi:10.1016/j.dnarep.2017.04.002

Cited by 12 publications

(4 citation statements)

References 88 publications

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“…and the ability for clonal propagation, which makes whole genome sequencing (WGS) practical. In previous studies we have described how C. elegans Y-family polymerases Polη and Polκ contribute to genomic stability [16][17][18]. Here, we investigate the contribution of REV1 and REV3 in suppressing genome alterations, and we address the redundancy between the different TLS enzymes by monitoring mutation accumulation in animals that lack either all C. elegans Y-family polymerases or all TLS activity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Bases within DNA are frequently damaged, producing obstacles to efficient and accurate DNA replication by replicative polymerases. Translesion synthesis (TLS) polymerases, via their ability to catalyze nucleotide additions to growing DNA chains across DNA lesions, promote replication of damaged DNA, thus preventing checkpoint activation, genome instability and cell death. In this study, we used C. elegans to determine the contribution of TLS activity on long-term stability of an animal genome. We monitored and compared the types of mutations that accumulate in REV1, REV3, POLH1 and POLK deficient animals that were grown under unchallenged conditions. We also addressed redundancies in TLS activity by combining all deficiencies. Remarkably, animals that are deficient for all Y-family polymerases as well as animals that have lost all TLS activity are viable and produce progeny, demonstrating that TLS is not essential for animal life. Whole genome sequencing analyses, however, reveal that TLS is needed to prevent genomic scars from accumulating. These scars, which are the product of polymerase theta-mediated end joining (TMEJ), are found overrepresented at guanine bases, consistent with TLS suppressing DNA double-strand breaks (DSBs) from occurring at replication-blocking guanine adducts. We found that in C. elegans, TLS across spontaneous damage is predominantly error free and anti-clastogenic, and thus ensures preservation of genetic information.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Caenorhabditis elegans were grown at 20°C on NGM plates with E. coli strain OP50 ( 21 ) and grown in light protected incubators to minimize DNA lesions resulting from visible light ( 22 ). Strains used were (see Supplementary Table S1 ): N2 (Bristol, Wild type); RB1801, csb-1(ok2335) X.; CB4037, glp-1(e2141) III., BJS259, glp-1(e2141) ; csb-1(ok2335) ; to image and measure mitochondrial mass we used SJ4103, zcls14 [myo-3::GFP(mit)] and SJ4143, zcls17 [ges-1::GFP(mit)], and created BJS348, zcls14[myo-3::GFP(mit)];csb-1(ok2335) , BJS332, zcls17[ges-1::GFP(mit)];csb-1(ok2335) double-mutants.…”

Section: Methodsmentioning

confidence: 99%

A C. elegans model for neurodegeneration in Cockayne syndrome

Lopes

Bożek

Herholz

et al. 2020

Nucleic Acids Research

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Cockayne syndrome (CS) is a congenital syndrome characterized by growth and mental retardation, and premature ageing. The complexity of CS and mammalian models warrants simpler metazoan models that display CS-like phenotypes that could be studied in the context of a live organism. Here, we provide a characterization of neuronal and mitochondrial aberrations caused by a mutation in the csb-1 gene in Caenorhabditis elegans. We report a progressive neurodegeneration in adult animals that is enhanced upon UV-induced DNA damage. The csb-1 mutants show dysfunctional hyperfused mitochondria that degrade upon DNA damage, resulting in diminished respiratory activity. Our data support the role of endogenous DNA damage as a driving factor of CS-related neuropathology and underline the role of mitochondrial dysfunction in the disease.

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“…A Pol θ defect in C. elegans only confers increased sensitivity to UV radiation if cells are additionally defective in nucleotide excision repair and Pol η, the major TLS enzyme for UV radiation-induced photoproducts. In this situation, the UV radiation sensitivity of the triple mutant can arise from a defect in TMEJ rather than a bypass of DNA damage (113).…”

Section: Can All Phenotypes Of Polq Disruption Be Explained By a Thet...mentioning

confidence: 99%

Genome Protection by DNA Polymerase θ

Wood

Doublié

2022

Annu. Rev. Genet.

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DNA polymerase θ (Pol θ) is a DNA repair enzyme widely conserved in animals and plants. Pol θ uses short DNA sequence homologies to initiate repair of double-strand breaks by theta-mediated end joining. The DNA polymerase domain of Pol θ is at the C terminus and is connected to an N-terminal DNA helicase–like domain by a central linker. Pol θ is crucial for maintenance of damaged genomes during development, protects DNA against extensive deletions, and limits loss of heterozygosity. The cost of using Pol θ for genome protection is that a few nucleotides are usually deleted or added at the repair site. Inactivation of Pol θ often enhances the sensitivity of cells to DNA strand–breaking chemicals and radiation. Since some homologous recombination–defective cancers depend on Pol θ for growth, inhibitors of Pol θ may be useful in treating such tumors. Expected final online publication date for the Annual Review of Genetics, Volume 56 is November 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Combined loss of three DNA damage response pathways renders C. elegans intolerant to light

Cited by 12 publications

References 88 publications

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

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

A C. elegans model for neurodegeneration in Cockayne syndrome

Genome Protection by DNA Polymerase θ

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