Human Molecular Genetics Advance Access originally published online on August 27, 2004
Human Molecular Genetics 2004 13(20):2399-2408; doi:10.1093/hmg/ddh271
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Human Molecular Genetics, Vol. 13, No. 20 © Oxford University Press 2004; all rights reserved
Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA and 2Department of Molecular and Cellular Physiology, Stanford School of Medicine, Beckman Center, Stanford, CA 94305, USA
Received May 27, 2004; Accepted August 18, 2004
Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant cancer predisposition syndrome, the gene for which encodes a nuclear protein, menin. The biochemical function of this protein has not been completely elucidated, but several studies have shown a role in transcriptional modulation through recruitment of histone deacetylase. The mechanism by which MEN1 mutations cause tumorigenesis is unknown. The Drosophila homolog of MEN1, Mnn1, encodes a protein 50% identical to human menin. In order to further elucidate the function of MEN1, we generated a null allele of this gene in Drosophila and showed that homozygous inactivation results in morphologically normal flies that are hypersensitive to ionizing radiation and two DNA cross-linking agents, nitrogen mustard and cisplatinum. The spectrum of agents to which mutant flies are sensitive and analysis of the molecular mechanisms of this sensitivity suggest a defect in nucleotide excision repair. Drosophila Mnn1 mutants have an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats, a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. Our data indicate that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA and HNPCC genes.
* To whom correspondence should be addressed at: Department of Genetics, Box 208005, SHM I-321, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8005, USA. Tel: +1 2037855749; Fax: +1 2037857227; Email: allen.bale{at}yale.edu
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