Isolation of yeast mutants sensitive to the bifunctional alkylating agent nitrogen mustard

Ruhland, A.; Haase, Eckard; Siede, Wolfram; Brendel, Martin

doi:10.1007/bf00425609

Cited by 77 publications

(37 citation statements)

References 16 publications

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“…The in vitro activity of FAN1 on substrates containing an ICL overlaps with the activity of SNM1A, one of the three human homologs of Pso2, a nuclease that functions in ICL repair in Saccharomyces cerevisiae (Henriques and Moustacchi 1980;Ruhland et al 1981;Hejna et al 2007;Wang et al 2011). Mammalian SNM1A shares the most similarity with Pso2 and is the only homolog that can complement the ICL sensitivity of pso2Δ yeast (Hazrati et al 2008).…”

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confidence: 99%

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

et al. 2016

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Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitinbinding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5 ′ -3 ′ exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit + cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency.

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Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

et al. 2016

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“…The Saccharomyces cerevisiae PSO2/SNM1 gene was identified in genetic screens for novel genes involved in the repair of ICLs produced by psoralen-UVA and nitrogen mustard (HN2), respectively (29,56,57). S. cerevisiae cells defective in PSO2 are uniquely sensitive to ICL-forming agents (including HN2, cisplatin, mitomycin C, and psoralens) but demonstrate wild-type resistance to monofunctional alkylating agents and ionizing radiation (57).…”

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DNA Interstrand Cross-Link Repair in theSaccharomyces cerevisiaeCell Cycle: Overlapping Roles forPSO2(SNM1) with MutS Factors andEXO1during S Phase

Barber

Ward

Hartley

et al. 2005

Molecular and Cellular Biology

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Pso2/Snm1 is a member of the ␤-CASP metallo-␤-lactamase family of proteins that include the V(D)J recombination factor Artemis. Saccharomyces cerevisiae pso2 mutants are specifically sensitive to agents that induce DNA interstrand cross-links (ICLs). Here we establish a novel overlapping function for PSO2 with MutS mismatch repair factors and the 5-3 exonuclease Exo1 in the repair of DNA ICLs, which is confined to S phase. Our data demonstrate a requirement for NER and Pso2, or Exo1 and MutS factors, in the processing of ICLs, and this is required prior to the repair of ICL-induced DNA double-strand breaks (DSBs) that form during replication. Using a chromosomally integrated inverted-repeat substrate, we also show that loss of both pso2 and exo1/msh2 reduces spontaneous homologous recombination rates. Therefore, PSO2, EXO1, and MSH2 also appear to have overlapping roles in the processing of some forms of endogenous DNA damage that occur at an irreversibly collapsed replication fork. Significantly, our analysis of ICL repair in cells synchronized for each cell cycle phase has revealed that homologous recombination does not play a major role in the direct repair of ICLs, even in G 2 , when a suitable template is readily available. Rather, we propose that recombination is primarily involved in the repair of DSBs that arise from the collapse of replication forks at ICLs. These findings have led to considerable clarification of the complex genetic relationship between various ICL repair pathways.

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“…A number of snm and pso mutants have been isolated after screening for strains with increased sensitivity to nitrogen mustard and 8-methoxypsoralen plus UVA light, respectively (25,48). Some of the mutants isolated are sensitive to several classes of DNA-damaging agents, while others are almost exclusively sensitive to ICL agents.…”

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Disruption of Mouse SNM1 Causes Increased Sensitivity to the DNA Interstrand Cross-Linking Agent Mitomycin C

Dronkert

Wit

Boeve

et al. 2000

Molecular and Cellular Biology

117

110

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DNA interstrand cross-links (ICLs) represent lethal DNA damage, because they block transcription, replication, and segregation of DNA. Because of their genotoxicity, agents inducing ICLs are often used in antitumor therapy. The repair of ICLs is complex and involves proteins belonging to nucleotide excision, recombination, and translesion DNA repair pathways in Escherichia coli, Saccharomyces cerevisiae, and mammals. We cloned and analyzed mammalian homologs of the S. cerevisiae gene SNM1 (PSO2), which is specifically involved in ICL repair. Human Snm1, a nuclear protein, was ubiquitously expressed at a very low level. We generated mouse SNM1 ؊/؊ embryonic stem cells and showed that these cells were sensitive to mitomycin C. In contrast to S. cerevisiae snm1 mutants, they were not significantly sensitive to other ICL agents, probably due to redundancy in mammalian ICL repair and the existence of other SNM1 homologs. The sensitivity to mitomycin C was complemented by transfection of the human SNM1 cDNA and by targeting of a genomic cDNA-murine SNM1 fusion construct to the disrupted locus. We also generated mice deficient for murine SNM1. They were viable and fertile and showed no major abnormalities. However, they were sensitive to mitomycin C. The ICL sensitivity of the mammalian SNM1 mutant suggests that SNM1 function and, by implication, ICL repair are at least partially conserved between S. cerevisiae and mammals.

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Isolation of yeast mutants sensitive to the bifunctional alkylating agent nitrogen mustard

Cited by 77 publications

References 16 publications

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

DNA Interstrand Cross-Link Repair in theSaccharomyces cerevisiaeCell Cycle: Overlapping Roles forPSO2(SNM1) with MutS Factors andEXO1during S Phase

Disruption of Mouse SNM1 Causes Increased Sensitivity to the DNA Interstrand Cross-Linking Agent Mitomycin C

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