Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells

Abraham, Jacinth; Lemmers, Bénédicte; Hande, M. Prakash; Moynahan, Mary Ellen; Chahwan, Charly; Ciccia, Alberto; Essers, Jeroen; Hanada, Katsuhiro; Chahwan, Richard; Khaw, Aik Kia; McPherson, Peter S.; Shehabeldin, Amro; Laister, Rob C.; Arrowsmith, C.H.; Kanaar, Roland; West, Stephen C.; Jasin, Maria; Hakem, Razqallah

doi:10.1093/emboj/cdg580

Cited by 118 publications

(103 citation statements)

References 91 publications

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“…EME1 (fc: 11.366, DON5) cleaves branched DNA structures. In the absence of EME1, chromosomal aberrations occurred and led to genomic instability (Abraham et al, 2003). The gene RAD51L1 (fc: 11.395, DON2.5) functions in homologous recombination and DNA double-strand break repair (Miller et al, 2002).…”

Section: Dna Repairmentioning

confidence: 99%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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The effects of mycotoxins in the production of animal feed were investigated using broiler chickens. For the feeding trial, naturally Fusarium mycotoxin-contaminated wheat was used, which mainly contained deoxynivalenol (DON). The main effects of DON are reduction of the feed intake and reduced weight gain of broilers. At the molecular level, DON binds to the 60 S ribosomal subunit and subsequently inhibits protein synthesis at the translational level. However, little is known about other effects of DON, for example, at the transcriptional level. Therefore, a microarray analysis was performed, which allows the investigation of thousands of transcripts in one experiment. In the experiment, 20 broilers were separated into four groups of five broilers each at day 1 after hatching. The diets consisted of a control diet and three diets with calculated, moderate concentrations of 1.0, 2.5 and 5.0 mg DON/kg feed, which was attained by exchanging uncontaminated wheat with naturally mycotoxin-contaminated wheat up to the intended DON concentration. The broilers were held at standard conditions for 23 days. Three microarrays were used per group to determine the significant alterations of the gene expression in the liver (P , 0.05), and qPCR was performed on the liver and the jejunum to verify the results. No significant difference in BW, feed intake or feed conversion rate was observed. The nutrient uptake into the hepatic and jejunal cells seemed to be influenced by genes: SLC2A5 (fc: 21.54, DON2.5), which facilitates glucose and fructose transport and SLC7A10 (fc: 11.49, DON5), a transporter of D-serine and other neutral amino acids. In the jejunum, the palmitate transport might be altered by SLC27A4 (fc: 21.87, DON5) and monocarboxylates uptake by SLC16A1 (fc: 21.47, DON5). The alterations of the SLC gene expression may explain the reduced weight gain of broilers chronically exposed to DON-contaminated wheat. The decreased expressions of EIF2AK3 (fc: 21.29, DON2.5/5) and DNAJC3 (fc: 21.44, DON2.5) seem to be related to the translation inhibition. The binding of DON to the 60 S ribosomal subunit and the subsequent translation inhibition might be counterbalanced by the downregulation of EIF2AK3 and DNAJC3. The genes PARP1, MPG, EME1, XPAC, RIF1 and CHAF1B are mainly related to single-strand DNA modifications and showed an increased expression in the group with 5 mg DON/kg feed. The results indicate that significantly altered gene expression was already occurring at 2.5 mg DON/kg feed.

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Section: Dna Repairmentioning

confidence: 99%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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“…Kennedy and A.D. D'Andrea, unpubl.). This implies that another endonuclease such as the Mus81-Eme1 complex (Abraham et al 2003) is, at least partly, involved in the excision of DNA cross-links upstream in the FA pathway.…”

Section: Recruitment Of Dna Repair Proteinsmentioning

confidence: 99%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

359

344

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Over the past few years, study of the rare inherited chromosome instability disorder, Fanconi Anemia (FA), has uncovered a novel DNA damage response pathway. Through the cooperation of multiple proteins, this pathway regulates a complicated cellular response to DNA cross-linking agents and other genotoxic stresses. In this article we review recent data identifying new components of the FA pathway that implicate it in several aspects of the DNA damage response, including the direct processing of DNA, translesion synthesis, homologous recombination, and cell cycle regulation. We also discuss new findings that explain how the FA pathway is regulated through the processes of ubiquitination and deubiquitination. We then consider the clinical implications of our current understanding of the FA pathway, particularly in the development and treatment of malignancy in heterozygous carriers of FA mutations or in patients with sporadic cancers. We consider how recent studies of p53-mediated apoptosis and loss of p53 function in models of FA may help explain the clinical features of the disease and finally present a hypothesis to account for the specificity of the FA pathway in the response to DNA cross-links.

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“…The MUS81-MMS4 endonuclease is thought to create crossovers either by direct resolution of the Holliday junction (HJ) or by cleaving D-loops and half-HJ structures formed in a pre-HJ intermediate (Boddy et al 2001;Hollingsworth and Brill 2004;Gaskell et al 2007). Although the components of both pathways are present in mice and humans, genetic, cytological, and biochemical studies suggest that meiotic crossovers in the mouse occur primarily through an interference-dependent pathway involving MSH4-MSH5 and MLH1-MLH3 (Woods et al 1999;Lipkin et al 2002;Santucci-Darmanin et al 2002;Abraham et al 2003;Ciccia et al 2003).…”

mentioning

confidence: 99%

A Mutation in the Putative MLH3 Endonuclease Domain Confers a Defect in Both Mismatch Repair and Meiosis inSaccharomyces cerevisiae

2008

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Interference-dependent crossing over in yeast and mammalian meioses involves the mismatch repair protein homologs MSH4-MSH5 and MLH1-MLH3. The MLH3 protein contains a highly conserved metalbinding motif DQHA(X) 2 E(X) 4 E that is found in a subset of MLH proteins predicted to have endonuclease activities (Kadyrov et al. 2006). Mutations within this motif in human PMS2 and Saccharomyces cerevisiae PMS1 disrupted the endonuclease and mismatch repair activities of MLH1-PMS2 and MLH1-PMS1, respectively (Kadyrov et al. 2006(Kadyrov et al. , 2007Erdeniz et al. 2007). As a first step in determining whether such an activity is required during meiosis, we made mutations in the MLH3 putative endonuclease domain motif (-D523N, -E529K) and found that single and double mutations conferred mlh3-null-like defects with respect to meiotic spore viability and crossing over. Yeast two-hybrid and chromatography analyses showed that the interaction between MLH1 and mlh3-D523N was maintained, suggesting that the mlh3-D523N mutation did not disrupt the stability of MLH3. The mlh3-D523N mutant also displayed a mutator phenotype in vegetative growth that was similar to mlh3D. Overexpression of this allele conferred a dominant-negative phenotype with respect to mismatch repair. These studies suggest that the putative endonuclease domain of MLH3 plays an important role in facilitating mismatch repair and meiotic crossing over.

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Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells

Cited by 118 publications

References 91 publications

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

The Fanconi Anemia/BRCA pathway: new faces in the crowd

A Mutation in the Putative MLH3 Endonuclease Domain Confers a Defect in Both Mismatch Repair and Meiosis inSaccharomyces cerevisiae

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