Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency

Horton, Julie K.; Wilson, Samuel H.

doi:10.1016/j.dnarep.2006.10.016

Cited by 58 publications

(50 citation statements)

References 118 publications

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“…We next asked which DNA repair pathways were important in cells treated with FdUrd alone and FϩA by first focusing on BER, a pathway that repairs FdUrd-induced lesions Pettersen et al, 2011) and that requires functional PARP (Horton and Wilson, 2007). Consistent with previous results , depletion of XRCC1, a central scaffolding component of the BER pathway, sensitized OVCAR-8 cells to FdUrd alone (Fig.…”

Section: Brca1/2 and Rad51 Protect From Floxuridine And Abt-888 769supporting

confidence: 63%

Identification of DNA Repair Pathways That Affect the Survival of Ovarian Cancer Cells Treated with a Poly(ADP-Ribose) Polymerase Inhibitor in a Novel Drug Combination

et al. 2012

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Section: Brca1/2 and Rad51 Protect From Floxuridine And Abt-888 769supporting

confidence: 63%

Identification of DNA Repair Pathways That Affect the Survival of Ovarian Cancer Cells Treated with a Poly(ADP-Ribose) Polymerase Inhibitor in a Novel Drug Combination

et al. 2012

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“…Sign epistasis may be more frequently detected in complex traits, like MMS sensitivity, that are influenced by hundreds of genes (Begley et al 2002(Begley et al , 2004Horton and Wilson 2007). 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.…”

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

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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 ...

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“…MX reacts with and covalently modifies AP sites to nonspecifically inhibit enzymes that bind to AP sites (Rosa et al, 1991), including Ape1, DNA polymerase ␤ (Horton and Wilson, 2007), and other BER enzymes (Taverna et al, 2001). MX enhances the sensitivity of several cancer cell lines to TMZ and radiation .…”

Section: Introductionmentioning

confidence: 99%

Novel Small-Molecule Inhibitor of Apurinic/Apyrimidinic Endonuclease 1 Blocks Proliferation and Reduces Viability of Glioblastoma Cells

Bapat¹,

Glass²,

Luo³

et al. 2010

J Pharmacol Exp Ther

100

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Apurinic/apyrimidinic (AP) endonuclease 1 (Ape1) is an essential DNA repair protein that plays a critical role in repair of AP sites via base excision repair. Ape1 has received attention as a druggable oncotherapeutic target, especially for treating intractable cancers such as glioblastoma. The goal of this study was to identify small-molecule inhibitors of Ape1 AP endonuclease. For this purpose, a fluorescence-based high-throughput assay was used to screen a library of 60,000 small-molecule compounds for ability to inhibit Ape1 AP endonuclease activity. Four compounds with IC 50 values less than 10 M were identified, validated, and characterized. One of the most promising compounds, designated Ape1 repair inhibitor 03 [2,4,9-trimeth-]-naphthyridin-5-amine; AR03), inhibited cleavage of AP sites in vivo in SF767 glioblastoma cells and in vitro in whole cell extracts and inhibited purified human Ape1 in vitro. AR03 has low affinity for double-stranded DNA and weakly inhibits the Escherichia coli endonuclease IV, requiring a 20-fold higher concentration than for inhibition of Ape1. AR03 also potentiates the cytotoxicity of methyl methanesulfonate and temozolomide in SF767 cells. AR03 is chemically distinct from the previously reported small-molecule inhibitors of Ape1. AR03 is a novel small-molecule inhibitor of Ape1, which may have potential as an oncotherapeutic drug for treating glioblastoma and other cancers.

show abstract

Hypersensitivity phenotypes associated with genetic and synthetic inhibitor-induced base excision repair deficiency

Cited by 58 publications

References 118 publications

Identification of DNA Repair Pathways That Affect the Survival of Ovarian Cancer Cells Treated with a Poly(ADP-Ribose) Polymerase Inhibitor in a Novel Drug Combination

Identification of DNA Repair Pathways That Affect the Survival of Ovarian Cancer Cells Treated with a Poly(ADP-Ribose) Polymerase Inhibitor in a Novel Drug Combination

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

Novel Small-Molecule Inhibitor of Apurinic/Apyrimidinic Endonuclease 1 Blocks Proliferation and Reduces Viability of Glioblastoma Cells

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