title: Genetic interactions between HNT3/Aprataxin and RAD27/FEN1 suggest parallel pathways for 5' end processing during base excision repair.
abstract: Mutations in Aprataxin cause the neurodegenerative syndrome ataxia oculomotor apraxia type 1. Aprataxin catalyzes removal of adenosine monophosphate (AMP) from the 5' end of a DNA strand, which results from an aborted attempt to ligate a strand break containing a damaged end. To gain insight into which DNA lesions are substrates for Aprataxin action in vivo, we deleted the Saccharomyces cerevisiae HNT3 gene, which encodes the Aprataxin homolog, in combination with known DNA repair genes. While hnt3Delta single mutants were not sensitive to DNA damaging agents, loss of HNT3 caused synergistic sensitivity to H(2)O(2) in backgrounds that accumulate strand breaks with blocked termini, including apn1Delta apn2Delta tpp1Delta and ntg1Delta ntg2Delta ogg1Delta. Loss of HNT3 in rad27Delta cells, which are deficient in long-patch base excision repair (LP-BER), resulted in synergistic sensitivity to H(2)O(2) and MMS, indicating that Hnt3 and LP-BER provide parallel pathways for processing 5' AMPs. Loss of HNT3 also increased the sister chromatid exchange frequency. Surprisingly, HNT3 deletion partially rescued H(2)O(2) sensitivity in recombination-deficient rad51Delta and rad52Delta cells, suggesting that Hnt3 promotes formation of a repair intermediate that is resolved by recombination.
authors.affiliation: Centre de Recherche, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, QC H1T 2M4, Canada.
authors.forename: James M
authors.initials: JM
authors.lastname: Daley
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wilson
authors.forename: Dindial
authors.initials: D
authors.lastname: Ramotar
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D000478:Alkylation / Q000187:drug effects; D020134:Catalytic Domain; D053960:DNA Breaks / Q000187:drug effects; D004260:DNA Repair; D004271:DNA, Fungal / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D045585:Flap Endonucleases / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D017354:Point Mutation; D051135:Rad51 Recombinase / Q000235:genetics; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: C438188:APTX protein, human; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051721:Rad52 DNA Repair and Recombination Protein; D029701:Saccharomyces cerevisiae Proteins; D000249:Adenosine Monophosphate; D008741:Methyl Methanesulfonate; D006861:Hydrogen Peroxide; D051135:Rad51 Recombinase; D045585:Flap Endonucleases; C468323:RAD27 protein, S cerevisiae
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