Defining genetic factors that modulate intergenerational CAG repeat instability in Drosophila melanogaster.
Trinucleotide repeat instability underlies >20 human hereditary disorders. These diseases include many neurological and neurodegenerative situations, such as those caused by pathogenic polyglutamine (polyQ) domains encoded by expanded CAG repeats. Although mechanisms of instability have been intensely studied, our knowledge remains limited in part due to the lack of unbiased genome-wide screens in multicellular eukaryotes. Drosophila melanogaster displays triplet repeat instability with features that recapitulate repeat instability seen in patients with disease. Here we report an enhanced fly model with substantial instability based on a noncoding 270 CAG (UAS-CAG(270)) repeat construct under control of a germline-specific promoter. We find that expression of pathogenic polyQ protein modulates repeat instability of CAG(270) in trans, indicating that pathogenic-length polyQ proteins may globally modulate repeat instability in the genome in vivo. We further performed an unbiased genetic screen for novel modifiers of instability. These studies indicate that different aspects of repeat instability are under independent genetic control, and identify CG15262, a protein with a NOT2/3/5 conserved domain, as a modifier of CAG repeat instability in vivo.
Department of Biology and the Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6018, USA.
Joonil
J
Jung
Marijn T M
MT
van Jaarsveld
Shin-Yi
SY
Shieh
Kexiang
K
Xu
Nancy M
NM
Bonini
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D042822:Genomic Instability / Q000235:genetics*; D018398:Homeodomain Proteins / Q000737:chemistry; D006801:Humans; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008297:Male; D010455:Peptides / Q000235:genetics; D017434:Protein Structure, Tertiary; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D018911:Trinucleotide Repeats / Q000235:genetics*
D018398:Homeodomain Proteins; D019476:Insect Proteins; D010455:Peptides; C097188:polyglutamine