A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells.
Allelic deletions of 10q25-26 and 19q13.3-13.4 are the most common genetic alterations in glial tumors. We have identified a balanced t(10;19) reciprocal translocation in the A172 glioblastoma cell line which involves both critical regions on chromosomes 10 and 19. In addition, loss of an entire copy of chromosome 10 has occurred in this cell line suggesting that the translocation event may provide a highly specific critical inactivating event in a gene responsible for tumorigenesis. Positional cloning of this translocation breakpoint resulted in the identification of a novel chromosome 10 gene, WDR11, which is a member of the WD-repeat gene family. The WDR11 gene is ubiquitously expressed, including normal brain and glial tumors. WDR11 is composed of 29 exons distributed over 58 kilobases and oriented towards the telomere. The translocation resulted in deletion of exon 5 and consequently fusion of intron 4 of WDR11 to the 3' untranslated region of a novel member, ZNF320, of the Krüppel-like zinc finger gene family. Since ZNF320 is oriented toward the centromere of chromosome 19, both genes appeared on the same derivative chromosome der(10). The chimeric transcript encodes the WDR11 polypeptide, which is truncated after the second of six WD-repeats. ZNF320 is also expressed in A172 cells, although it is not clear if the translocation affects the expression of the altered gene because of the presence of another unrearranged gene on chromosome 19. We suggest that, because of its localization in a region frequently showing LOH and the observation of inactivation of this gene in glioblastoma cells, WDR11 is a candidate gene for the frequently proposed tumor suppressor gene in 10q25-26 which is involved in tumorigenesis of glial and other tumors showing frequent alterations in the distal 10q region.
Chernova
O B
OB
Center for Molecular Genetics, Lerner Research Institute /ND40, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Hunyadi
A
A
Malaj
E
E
Pan
H
H
Crooks
C
C
Roe
B
B
Cowell
J K
JK
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D015139:Blotting, Southern; D002879:Chromosomes, Human, Pair 10; D002888:Chromosomes, Human, Pair 19; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics*; D017353:Gene Deletion; D005909:Glioblastoma / Q000235:genetics*; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D017422:Sequence Analysis, DNA; D016615:Telomere; D014018:Tissue Distribution; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers; D000092468:Bromodomain Containing Proteins
D018076:DNA, Complementary; D019204:GTP-Binding Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C435527:WDR11 protein, human; D000092468:Bromodomain Containing Proteins