title: The Drosophila mus101 gene, which links DNA repair, replication and condensation of heterochromatin in mitosis, encodes a protein with seven BRCA1 C-terminus domains.
abstract: The mutagen-sensitive-101 (mus101) gene of Drosophila melanogaster was first identified 25 years ago through mutations conferring larval hypersensitivity to DNA-damaging agents. Other alleles of mus101 causing different phenotypes were later isolated: a female sterile allele results in a defect in a tissue-specific form of DNA synthesis (chorion gene amplification) and lethal alleles cause mitotic chromosome instability that can be observed genetically and cytologically. The latter phenotype presents as a striking failure of mitotic chromosomes of larval neuroblasts to undergo condensation of pericentric heterochromatic regions, as we show for a newly described mutant carrying lethal allele mus101(lcd). To gain further insight into the function of the Mus101 protein we have molecularly cloned the gene using a positional cloning strategy. We report here that mus101 encodes a member of the BRCT (BRCA1 C terminus) domain superfamily of proteins implicated in DNA repair and cell cycle checkpoint control. Mus101, which contains seven BRCT domains distributed throughout its length, is most similar to human TopBP1, a protein identified through its in vitro association with DNA topoisomerase IIbeta. Mus101 also shares sequence similarity with the fission yeast Rad4/Cut5 protein required for repair, replication, and checkpoint control, suggesting that the two proteins may be functional homologs.
authors.affiliation: CRC Cell Cycle Genetics Group, Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom.
authors.forename: R R
authors.initials: RR
authors.lastname: Yamamoto
authors.forename: J M
authors.initials: JM
authors.lastname: Axton
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: R D
authors.initials: RD
authors.lastname: Saunders
authors.forename: D M
authors.initials: DM
authors.lastname: Glover
authors.forename: D S
authors.initials: DS
authors.lastname: Henderson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics*; D002874:Chromosome Mapping; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D017344:Genes, Insect; D005804:Genes, Lethal; D006570:Heterochromatin / Q000235:genetics*; D007247:Infertility, Female / Q000235:genetics; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics; D007814:Larva; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010641:Phenotype; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014960:X Chromosome
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D006570:Heterochromatin; D019476:Insect Proteins; C416162:mus101 protein, Drosophila