Sensitivity of a S. cerevisiae RAD27 deletion mutant to DNA-damaging agents and in vivo complementation by the human FEN-1 gene

Hansen, Ryan J.; Friedberg, Errol C.; Reagan, Michael S.

doi:10.1016/s0921-8777(00)00056-2

Cited by 19 publications

(17 citation statements)

References 21 publications

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“…In S. cerevisiae, both DNA Pol4 (Bebenek et al 2005) and Trf4 (Gellon et al 2008) possess a 59-dRP lyase activity, but whether either contributes to BER in vivo has not been clearly established (McInnis et al 2002;Gellon et al 2008). The high MMS and H 2 O 2 sensitivity of yeast cells missing Fen1/Rad27 Hansen et al 2000), and the suppression of the MMS sensitivity of rad27D by APN1 deletion (Wu and Wang 1999), suggest that Rad27 is the main activity for removing 59-dRP (see Figure 1).…”

Section: Ap Endonucleasesmentioning

confidence: 99%

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

2013

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DNA repair mechanisms are critical for maintaining the integrity of genomic DNA, and their loss is associated with cancer predisposition syndromes. Studies in Saccharomyces cerevisiae have played a central role in elucidating the highly conserved mechanisms that promote eukaryotic genome stability. This review will focus on repair mechanisms that involve excision of a single strand from duplex DNA with the intact, complementary strand serving as a template to fill the resulting gap. These mechanisms are of two general types: those that remove damage from DNA and those that repair errors made during DNA synthesis. The major DNA-damage repair pathways are base excision repair and nucleotide excision repair, which, in the most simple terms, are distinguished by the extent of single-strand DNA removed together with the lesion. Mistakes made by DNA polymerases are corrected by the mismatch repair pathway, which also corrects mismatches generated when single strands of non-identical duplexes are exchanged during homologous recombination. In addition to the true repair pathways, the postreplication repair pathway allows lesions or structural aberrations that block replicative DNA polymerases to be tolerated. There are two bypass mechanisms: an error-free mechanism that involves a switch to an undamaged template for synthesis past the lesion and an error-prone mechanism that utilizes specialized translesion synthesis DNA polymerases to directly synthesize DNA across the lesion. A high level of functional redundancy exists among the pathways that deal with lesions, which minimizes the detrimental effects of endogenous and exogenous DNA damage.

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Section: Ap Endonucleasesmentioning

confidence: 99%

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

2013

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“…Human Fen1 protein shares 61% identity and 79% similarity with Saccharomyces cerevisiae Rad27 protein (Shen et al, 1998). Recent work has shown that expression of human Fen1 can correct a number of mutant phenotypes in rad27 deletion (rad27Δ) yeast cells, including sensitivity to DNAdamaging agents, high rates of recombination and mutation, and synthetic lethality with double-strand-break repair mutants (Hansen et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency of yeast FEN1 causes instability of expanded CAG/CTG tracts in a length-dependent manner

Yang

Freudenreich

2007

Gene

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Trinucleotide repeat diseases, such as Huntington's disease, are caused by the expansion of trinucleotide repeats above a threshold of about 35 repeats. Once expanded, the repeats are unstable and tend to expand further both in somatic cells and during transmission, resulting in a more severe disease phenotype. Flap endonuclease 1 (Fen1), has an endonuclease activity specific for 5' flap structures and is involved in Okazaki fragment processing and base excision repair. Fen1 also plays an important role in preventing instability of CAG/CTG trinucleotide repeat sequences, as the expansion frequency of CAG/CTG repeats is increased in FEN1 mutants in vitro and in yeast cells defective for the yeast homolog, RAD27. Here we have tested whether one copy of yeast FEN1 is enough to maintain CAG/CTG tract stability in diploid yeast cells. We found that CAG/CTG repeats are stable in RAD27 +/− cells if the tract is 70 repeats long and exhibit a slightly increased expansion frequency if the tract is 85 or 130 repeats long. However for CAG-155 tracts, the repeat expansion frequency in RAD27 +/− cells is significantly higher than in RAD27 +/+ cells. This data indicates that cells containing longer CAG/CTG repeats need more Fen1 protein to maintain tract stability and that maintenance of long CAG/CTG repeats is particularly sensitive to Fen1 levels. Our results may explain the relatively small effects seen in the Huntington's disease (HD) FEN1 +/− heterozygous mice and myotonic dystrophy type 1 (DM1) FEN1 +/− heterozygous mice, and suggest that inefficient flap processing by Fen1 could play a role in the continued expansions seen in humans with trinucleotide repeat expansion diseases.

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“…The human FEN-1 and yeast Rad27 protein are homologous, and the human enzyme can complement the defect of yeast null for Rad27 protein (22,23). Yet the features of expansion induced by loss of Rad27 in yeast are very different from those observed in human disease.…”

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confidence: 99%

Nuclease-Deficient FEN-1 Blocks Rad51/BRCA1-Mediated Repair and Causes Trinucleotide Repeat Instability

Spiro¹,

McMurray

2003

Molecular and Cellular Biology

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Previous studies have shown that expansion-prone repeats form structures that inhibit human flap endonuclease (FEN-1). We report here that faulty processing by FEN-1 initiates repeat instability in mammalian cells. Disease-length CAG tracts in Huntington's disease mice heterozygous for FEN-1 display a tendency toward expansions over contractions during intergenerational inheritance compared to those in homozygous wild-type mice. Further, with regard to human cells expressing a nuclease-defective FEN-1, we provide direct evidence that an unprocessed FEN-1 substrate is a precursor to instability. In cells with no endogenous defects in DNA repair, exogenous nuclease-defective FEN-1 causes repeat instability and aberrant DNA repair. Inefficient flap processing blocks the formation of Rad51/BRCA1 complexes but invokes repair by other pathways.

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Sensitivity of a S. cerevisiae RAD27 deletion mutant to DNA-damaging agents and in vivo complementation by the human FEN-1 gene

Cited by 19 publications

References 21 publications

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

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

Haploinsufficiency of yeast FEN1 causes instability of expanded CAG/CTG tracts in a length-dependent manner

Nuclease-Deficient FEN-1 Blocks Rad51/BRCA1-Mediated Repair and Causes Trinucleotide Repeat Instability

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