High rate of CAD gene amplification in human cells deficient in MLH1 or MSH6.
MutS and MutL homologs have been implicated in multiple genetic stabilization pathways. The activities participate in the correction of DNA biosynthetic errors, are involved in cellular responses to certain types of DNA damage, and serve to ensure the fidelity of genetic recombination. We show here that the rate of CAD (carbamyl-P synthetase/aspartate transcarbamylase/dihydroorotase) gene amplification is elevated 50- to 100-fold in human cell lines deficient in MLH1 or MSH6, as compared with mismatch repair-proficient control cells. Fluorescence in situ hybridization indicates that these amplification events are the probable consequence of unequal sister chromatid exchanges involving chromosome 2, as well as translocation events involving other chromosomes. These results implicate MutS alpha and MutL alpha in the suppression of gene amplification and suggest that defects in this genetic stabilization function may contribute to the cancer predisposition associated with mismatch repair deficiency.
Chen
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The Howard Hughes Medical Institute and Department of Biochemistry, Box 3711, Duke University Medical Center, Durham, NC 27710, USA.
Bigner
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Modrich
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D048868:Adaptor Proteins, Signal Transducing; D001221:Aspartate Carbamoyltransferase / Q000235:genetics*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D020137:Base Pair Mismatch; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics*; D002352:Carrier Proteins; D002460:Cell Line; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004080:Dihydroorotase / Q000235:genetics*; D004351:Drug Resistance; D005784:Gene Amplification; D016158:Genes, p53; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D009097:Multienzyme Complexes / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; C033626:CAD trifunctional enzyme; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D000070957:MutL Protein Homolog 1; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D010746:Phosphonoacetic Acid