The drosophila mus101 gene, which links DNA repair, replication and condensation of heterochromatin in mitosis, encodes a protein with seven BRCA1 C-terminus domains

The mutagen-sensitive-101 (mus101) gene of Drosophila melanogaster was firs t identified 25 pears ago through mutations conferring larval hypersensitiv ity to DNA-damaging agents. Other alleles of mus101 causing different pheno types were later isolated: a female sterile allele results in a defect in a tissue-specific form of DNA synthesis (chorion gene amplification) and let hal alleles cause mitotic chromosome instability that can be observed genet ically and cytologically. The latter phenotype presents as a striking failu re of mitotic chromosomes of larval neuroblasts to undergo condensation of pericentric heterochromatic regions, as we show for a newly described mutan t carrying lethal allele mus101(lcd). To gain further insight into the func tion of the Mus101 protein we have molecularly cloned the gene using a posi tional cloning strategy. We report here that mus101 encodes a member of the BRCT (BRCA1 C terminus) domain superfamily of proteins implicated in DNA r epair 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 topoisomera se II beta. Mus101 also shares sequence similarity with the fission yeast R ad4/Cut5 protein required for repair, replication, and checkpoint control, suggesting that the two proteins may be functional homologs.