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Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1.
Hum Mol Genet. 2004 Oct 15; 13(20):2399-408.HM

Abstract

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.

Authors+Show Affiliations

Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15333582

Citation

Busygina, Valeria, et al. "Hypermutability in a Drosophila Model for Multiple Endocrine Neoplasia Type 1." Human Molecular Genetics, vol. 13, no. 20, 2004, pp. 2399-408.
Busygina V, Suphapeetiporn K, Marek LR, et al. Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1. Hum Mol Genet. 2004;13(20):2399-408.
Busygina, V., Suphapeetiporn, K., Marek, L. R., Stowers, R. S., Xu, T., & Bale, A. E. (2004). Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1. Human Molecular Genetics, 13(20), 2399-408.
Busygina V, et al. Hypermutability in a Drosophila Model for Multiple Endocrine Neoplasia Type 1. Hum Mol Genet. 2004 Oct 15;13(20):2399-408. PubMed PMID: 15333582.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1. AU - Busygina,Valeria, AU - Suphapeetiporn,Kanya, AU - Marek,Lorri R, AU - Stowers,R Steven, AU - Xu,Tian, AU - Bale,Allen E, Y1 - 2004/08/27/ PY - 2004/8/31/pubmed PY - 2005/4/26/medline PY - 2004/8/31/entrez SP - 2399 EP - 408 JF - Human molecular genetics JO - Hum Mol Genet VL - 13 IS - 20 N2 - 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. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/15333582/Hypermutability_in_a_Drosophila_model_for_multiple_endocrine_neoplasia_type_1_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddh271 DB - PRIME DP - Unbound Medicine ER -