DNA Repair Mechanisms and the Bypass of DNA Damage in <i>Saccharomyces cerevisiae</i>

Boiteux, Serge; Jinks-Robertson, Sue

doi:10.1534/genetics.112.145219

Cited by 203 publications

(230 citation statements)

References 489 publications

(533 reference statements)

Supporting

Mentioning

215

Contrasting

Unclassified

Order By: Relevance

“…Repair of MMS lesions involves pathways including base excision repair (Boiteux and Jinks-Robertson 2013), double strand break repair (Symington et al 2014), chromatin remodeling (Oum et al 2011) pathways, etc. Mutations in these genes will likely result in altered sensitivity to MMS.…”

Section: Loss Of Heterozygosity In Candida Albicansmentioning

confidence: 99%

Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans

et al. 2016

View full text Add to dashboard Cite

By testing the susceptibility to DNA damaging agents of several Candida albicans mutant strains derived from the commonly used laboratory strain, CAI4, we uncovered sensitivity to methyl methanesulfonate (MMS) in CAI4 and its derivatives, but not in CAF2-1. This sensitivity is not a result of URA3 disruption because the phenotype was not restored after URA3 reintroduction. Rather, we found that homozygosis of a short region of chromosome 3R (Chr3R), which is naturally heterozygous in the MMS-resistant-related strains CAF4-2 and CAF2-1, confers MMS sensitivity and modulates growth polarization in response to MMS. Furthermore, induction of homozygosity in this region in CAF2-1 or CAF4-2 resulted in MMS sensitivity. We identified 11 genes by SNP/comparative genomic hybridization containing only the a alleles in all the MMS-sensitive strains. Four candidate genes, SNF5, POL1, orf19.5854.1, and MBP1, were analyzed by generating hemizygous configurations in CAF2-1 and CAF4-2 for each allele of all four genes. Only hemizygous MBP1a/mbp1b::SAT1-FLIP strains became MMS sensitive, indicating that MBP1a in the homo-or hemizygosis state was sufficient to account for the MMS-sensitive phenotype. In yeast, Mbp1 regulates G1/S genes involved in DNA repair. A second region of homozygosis on Chr2L increased MMS sensitivity in CAI4 (Chr3R homozygous) but not CAF4-2 (Chr3R heterozygous). This is the first example of sign epistasis in C. albicans.KEYWORDS Candida albicans; LOH; MMS susceptibility; MBP1; growth polarization T HE opportunistic fungal pathogen Candida albicans is often isolated as a highly heterozygous diploid; the genome of the reference strain SC5314 has 67,500 single nucleotide polymorphisms (SNPs) (Jones et al. 2004;Braun et al. 2005;Muzzey et al. 2013). SNPs found within regulatory regions can affect transcription levels between the alleles (Staib et al. 2002). Even synonymous SNPs residing in open reading frames (ORFS) can result in differences in the rate and efficiency of messenger RNA (mRNA) translation since poorly used codons delay protein synthesis. These delays may lead to misfolding of the nascent protein or formation of mRNA secondary structures (reviewed in Larriba and Calderone 2008). Recent genome-wide analysis of cis elements on gene expression showed that allele-specific effects are often due to mRNA levels and/or translation efficiency (Muzzey et al. 2014).While the majority of SNPs reside in intergenic regions, more than half of open reading frames contain one or more SNPs. The vast majority (78%) of these are nonsynonymous, implying that a significant fraction of ORFs encode proteins that differ in one or more amino acids (Jones et al. 2004) that may affect crucial properties. Nonconservative amino acid substitutions within an enzyme's catalytic domain could result in an inactive allele (Gómez-Raja et al. 2008). However, many SNPs will cause only minor or insignificant alterations in protein properties.Mitotic recombination or less frequently, chromosome truncation or loss, will reveal ...

show abstract

Section: Loss Of Heterozygosity In Candida Albicansmentioning

confidence: 99%

Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Other conserved repair mechanisms involve recombinatorial repair strategies, such as the homologous recombination, the non-homologous end-joining (NHEJ), and the interstrand cross-linked repair (ICL) systems (Boiteux and Jinks-Robertson, 2013). Homologous recombination underlies processes for the repair of DNA double-strand breaks (DSBs), maintenance of rDNA copy number and rescue of collapsed replication forks.…”

Section: Introductionmentioning

confidence: 99%

Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators

Pijuan

Carlos

Herrero

et al. 2015

Journal of Cell Science

View full text Add to dashboard Cite

Fe-S cluster biogenesis machinery is required for multiple DNA metabolism processes. In this work, we show that, in Saccharomyces cerevisiae, defects at different stages of the mitochondrial Fe-S cluster assembly machinery (ISC) result in increased spontaneous mutation rate and hyper-recombination, accompanied by an increment in Rad52-associated DNA repair foci and a higher phosphorylated state of γH2A histone, altogether supporting the presence of constitutive DNA lesions. Furthermore, ISC assembly machinery deficiency elicits a DNA damage response that upregulates ribonucleotide reductase activity by promoting the reduction of Sml1 levels and the cytosolic redistribution of Rnr2 and Rnr4 enzyme subunits. Depending on the impaired stage of the ISC machinery, different signaling pathway mediators contribute to such a response, converging on Dun1. Thus, cells lacking the glutaredoxin Grx5, which are compromised at the core ISC system, show Mec1-and Rad53-independent Dun1 activation, whereas both Mec1 and Chk1 are required when the non-core ISC member Iba57 is absent. Grx5-null cells exhibit a strong dependence on the error-free postreplication repair and the homologous recombination pathways, demonstrating that a DNA damage response needs to be activated upon ISC impairment to preserve cell viability.

show abstract

“…Both subpathways of Rad18-dependent DDT are important during exposure to chronic damage The DDT pathway regulated by the Rad6-Rad18 complex is composed of two subpathways: an error-prone pathway mediated by TLS polymerases and an error-free pathway that requires Rad5 and the Ubc13-Mms2 complex (reviewed by Boiteux and Jinks-Robertson 2013). The importance of error-free DDT for survival during CLUV treatment was previously inferred through analyses of rad18D and rad5D single mutants; loss of TLS alone (rev1D rev3D rad30D triple mutant) did not affect survival (Hishida et al 2009).…”

Section: Resultsmentioning

confidence: 99%

“…Saccharomyces cerevisiae has served as a model for elucidating the genetic control and basic mechanisms of DDT in eukaryotes (reviewed by Boiteux and Jinks-Robertson 2013). Central to regulating DDT are post-translational modifications to PCNA, the sliding clamp that promotes processivity of replicative DNA polymerases and serves as a landing pad for numerous proteins involved in DNA metabolism (reviewed by Moldovan et al 2007).…”

mentioning

confidence: 99%

Shared Genetic Pathways Contribute to the Tolerance of Endogenous and Low-Dose Exogenous DNA Damage in Yeast

Lehner

Jinks-Robertson

2014

Genetics

Self Cite

View full text Add to dashboard Cite

DNA damage that escapes repair and blocks replicative DNA polymerases is tolerated by bypass mechanisms that fall into two general categories: error-free template switching and error-prone translesion synthesis. Prior studies of DNA damage responses in Saccharomyces cerevisiae have demonstrated that repair mechanisms are critical for survival when a single, high dose of DNA damage is delivered, while bypass/tolerance mechanisms are more important for survival when the damage level is low and continuous (acute and chronic damage, respectively). In the current study, epistatic interactions between DNA-damage tolerance genes were examined and compared when haploid yeast cells were exposed to either chronic ultraviolet light or chronic methyl methanesulfonate. Results demonstrate that genes assigned to error-free and error-prone bypass pathways similarly promote survival in the presence of each type of chronic damage. In addition to using defined sources of chronic damage, rates of spontaneous mutations generated by the Pol z translesion synthesis DNA polymerase (complex insertions in a frameshift-reversion assay) were used to infer epistatic interactions between the same genes. Similar epistatic interactions were observed in analyses of spontaneous mutation rates, suggesting that chronic DNA-damage responses accurately reflect those used to tolerate spontaneous lesions. These results have important implications when considering what constitutes a safe and acceptable level of exogenous DNA damage. D AMAGE to cellular DNA that results from normal metabolic processes is classified as spontaneous, while that resulting from exogenous physical or chemical agents is considered induced. Spontaneous damage occurs at low, continuous levels and hence is chronic in nature. Though induced damage is typically delivered in a single, acute dose, it can also be chronic, with examples including daily exposure to solar radiation or cigarette smoke. Spontaneous and induced damage are dealt with by two general, evolutionarily conserved mechanisms: one that permanently removes the damage and one that temporarily bypasses the damage, allowing it to be tolerated (for a general overview, see Ciccia and Elledge 2010). Most damage removal occurs via conserved excision repair pathways, but a small number of damages can be directly reversed enzymatically (e.g., thymine-thymine dimer reversal by photolyase). Damage removal by excision repair generates a single-strand gap that is filled using the complementary, undamaged strand as a template and hence is a high-fidelity process. Such repair only operates, however, when a relevant lesion is present in double-strand DNA. Damage that escapes repair and is encountered during replication can block the progress of DNA synthesis, leading to the formation of a single-strand gap opposite the lesion, replication fork collapse, cell-cycle arrest, and/or death. DNA-damage bypass/tolerance pathways thus become critically important during S and G2 phases, as these allow completion of replication and ...

show abstract

DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae

Cited by 203 publications

References 489 publications

Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans

Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans

Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators

Shared Genetic Pathways Contribute to the Tolerance of Endogenous and Low-Dose Exogenous DNA Damage in Yeast

Contact Info

Product

Resources

About